Curcumin Analogs and Methods of Making and Using Thereof

ABSTRACT

Compounds having Formula I or II, and methods of making and using thereof, are described herein:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government Support under Agreement Nos.GM086925 and GM084933 awarded to Binghe Wang by the National Institutesof Health. The Government has certain rights in the invention.

FIELD OF THE INVENTION

This invention is in the field of curcumin analogs, particularly C5curcumin analogs, pharmaceutical compositions containing the same, andmethods of using thereof.

BACKGROUND OF THE INVENTION

Turmeric has been used since ancient times in India and China as adietary pigment and essential spice. It is also used in traditional/folkmedicine as an antiseptic and anti-inflammatory agent and in woundhealing. Curcumin has been identified as the active ingredient inturmeric. It is a yellow colored polyphenolic natural compound isolatedfrom the rhizome of the herb Curcuma longa Linn which exhibits variousbiological activities including anti-inflammatory, antioxidant,antimicrobial, antiviral, chemopreventive, antiangiogenic, andanticancer activities. Curcumin has also shown hepato-protective andnephro-protective, thrombosis supressing, myocardial infarctionprotective, hypoglycemic, and antirheumatic activities.

Curcumin exhibits this wide range of biological activities due to itsunique ability to interact with various biomolecules and biochemicalpathways, which include cell proliferation pathways, caspase activationpathways, tumor suppressor pathways, transcriptional factors, cellsurvival pathways, mitochondrial pathways, protein kinase pathways, anddeath receptor pathways. The multi-targeting ability of curcumin hasmade it a focus for cancer chemoprevention and pharmacotherapy.

Toxicological studies conducted in animal models or in humans have shownthat curcumin is safe even at a dose level of 12 g/d. Thepharmacological safety and efficacy of curcumin makes it a potentialcompound for treatment and prevention of a wide variety of diseases.However, the poor solubility, poor bioavailability, and poor absorptionas well as rapid metabolism are major problems associated with curcumin.Consequently, curcumin itself is not a good candidate for furtherclinical development. Much effort has been devoted to developing newcurcumin analogues in order to solve the pharmacokinetic problems and atthe same time to maintain high potency and low toxicity. Efforts havealso been made to enhance its selectivity and potency for addressing thepathological diversity of human cancer.

In order to address these issues, numerous approaches have been exploredto synthesize curcumin analogues and derivatives. The pharmacologicalstudies conducted on curcumin indicate that the β-diketone functionalityof curcumin is a substrate for liver aldoketo reductases and this may bea metabolism of curcumin in vivo. In order to improve the in vivometabolic stability of curcumin (e.g., C7 curcuminoids), severalcurcumin analogues with a single carbonyl moiety (e.g., C5 curcuminoids)have been prepared and some of these compounds have exhibited anticanceractivity.

The degree of in vivo degradation and pharmacokinetic studies suggestthat these compounds are more stable and exhibit increased activitycompared to curcumin. Structure activity relationship studies conductedon these compounds revealed that the heteroaromatic core in thesecompounds correlated with high anti-proliferative and anti-inflammatoryactivities.

There exists a need for the synthesis of new C5 curcumin analogues,which are stable, bioavailable, and exhibit the desired biologicalactivity.

Accordingly, it is an object of the invention to provide new stable,bioavailable C5 curcumin analogues and exhibit the desired biologicalactivity, and methods of making and using thereof.

SUMMARY OF THE INVENTION

The compounds described herein are compounds of Formula

R₁-R₁₀ are independently absent or selected from the group consisting ofsubstituted or unsubstituted, linear, branched, or cyclic alkyl,alkenyl, or alkynyl; halogen, substituted or unsubstituted aryl orheteroaryl, substituted or unsubstituted alkoxy; hydroxy, cyano, formyl,acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primary amide (e.g.,—CONH₂), secondary amide (e.g., —CONHR₁₂), tertiary amide (e.g.,—CONR₁₂R₁₂), secondary carbamate (e.g., —OCONHR₁₂; —NHCOOR₁₂), tertiarycarbamate (e.g., —OCONR₁₂R₁₂; —NR₁₂COOR₁₂), urea (e.g., —NHCONHR₁₂;—NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂), carbinol (e.g., —CH₂OH;—CHR₁₂OH, —CR₁₂R₁₂OH), ester (e.g., —COOR₁₂), thiol (—SH), primary amine(—NH₂), secondary amine (e.g., —NHR₁₂), tertiary amine (e.g., —NR₁₂R₁₂),thioether (e.g., —SR₁₂), AND sulfinyl group (e.g., —SOR₁₂), sulfonylgroup (e.g., —SOOR₁₂).

R₁₁ is substituted or unsubstituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, or alkynyl; substituted or unsubstituted benzyl sulfonyl(Bnz); substituted or unsubstituted p-toluene sulfonyl (p-Ts);substituted or unsubstituted benzyl; substituted or unsubstituted aryl;substituted or unsubstituted heteroaryl; wherein the R₁₁ if substituted,can be substituted with one or more of alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkoxy, amine, halogen, hydroxyl, nitrile, CF₃, ester,amide, urea, carbamate, thioether, carboxylic acid, and aryl; and

L is a linker or spacer.

In some embodiments, R₁₁ is unsubstituted alkyl, such as methyl, ethyl,or propyl. In some embodiments, R₁₁ is unsubstituted ethyl and at leastone of R₁-R₅ and at least one of R₆-R₁₀ are halogen (e.g., Br, Cl, orF). In particular embodiments, R₁₁ and R₈ are halogen and R₁, R₂, R₄-R₇,R₉, and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ arethe same halogen. In still other embodiments, R₁₁ is unsubstituted ethyland at least one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstitutedalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl.In particular embodiments, R₃ and R₈ are unsubstituted alkyl and R₁, R₂,R₄-R₇, R₉, and R₁₀ are hydrogen. In more particular embodiments, R₃ andR₈ are the same unsubstituted alkyl. In still other embodiments, R₁₁ isunsubstituted ethyl and at least one of R₁-R₅ and at least one of R₆-R₁₀are unsubstituted alkoxy, such as methoxy. In particular embodiments, R₃and R₈ are unsubstituted alkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ arehydrogen. In more particular embodiments, R₃ and R₈ are the sameunsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted p-toluene sulfonyl. In someembodiments, R₁₁ is unsubstituted p-toluene sulfonyl and at least one ofR₁-R₅ and at least one of R₆-R₁₀ are halogen (e.g., Br, Cl, or F). Inparticular embodiments, R₃ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, andR₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are the samehalogen. In still other embodiments, R₁₁ is unsubstituted p-toluenesulfonyl and at least one of R₁-R₅ and at least one of R₆-R₁₀ areunsubstituted alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, or t-butyl. In particular embodiments, R₃ and R₈ areunsubstituted alkyl and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In moreparticular embodiments, R₃ and R₈ are the same unsubstituted alkyl. Instill other embodiments, R₁₁ is unsubstituted p-toluene sulfonyl and atleast one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstituted alkoxy,such as methoxy. In particular embodiments, R₃ and R₈ are unsubstitutedalkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In more particularembodiments, R₃ and R₈ are the same unsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted benzyl. In some embodiments,R₁₁ is unsubstituted benzyl and at least one of R₁-R₅ and at least oneof R₆-R₁₀ are halogen (e.g., Br, Cl, or F). In particular embodiments,R₃ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. Inmore particular embodiments, R₃ and R₈ are the same halogen. In stillother embodiments, R₁₁ is unsubstituted benzyl and at least one of R₁-R₅and at least one of R₆-R₁₀ are unsubstituted alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In particularembodiments, R₃ and R₈ are unsubstituted alkyl and R₁, R₂, R₄-R₇, R₉,and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are thesame unsubstituted alkyl. In still other embodiments, R₁₁ isunsubstituted benzyl and at least one of R₁-R₅ and at least one ofR₆-R₁₀ are unsubstituted alkoxy, such as methoxy. In particularembodiments, R₃ and R₈ are unsubstituted alkoxy and R₁, R₂, R₄-R₇, R₉,and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are thesame unsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted benzyl sulfonyl. In someembodiments, R₁₁ is unsubstituted benzyl sulfonyl, at least one of R₁-R₅and at least one of R₆-R₁₀ are halogen (e.g., Br, Cl, or F). Inparticular embodiments, R₃ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, andR₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are the samehalogen. In still other embodiments, R₁₁ is unsubstituted benzylsulfonyl and at least one of R₁-R₅ and at least one of R₆-R₁₀ areunsubstituted alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, or t-butyl. In particular embodiments, R₃ and R₈ areunsubstituted alkyl and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In moreparticular embodiments, R₃ and R₈ are the same unsubstituted alkyl. Instill other embodiments, R₁₁ is unsubstituted benzyl sulfonyl and atleast one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstituted alkoxy,such as methoxy. In particular embodiments, R₃ and R₈ are unsubstitutedalkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In more particularembodiments, R₃ and R₈ are the same unsubstituted alkoxy.

In still other embodiments, L is present and R₁₁ is a substituted orunsubstituted aryl or heteroaryl group. In particular embodiments, L isa substituted or unsubstituted alkylene group, such as a methylenegroup, and R₁₁ is a substituted or unsubstituted triazole. In someembodiments, L is an alkylene groups, such as substituted orunsubstituted methylene linker and R₁₁ is a triazole group, such as

wherein L is attached to the triazole group at the C5 position. In someembodiments, the triazole ring is substituted at the nitrogen as shownabove. In particular embodiments, the triazole ring is substituted witha substituted alkyl group. In more particular embodiments, the alkylgroup is substituted as shown below:

In still other embodiments, the compound has the following formula:

wherein R₁-R₁₀ are independently absent or selected from the groupconsisting of substituted or unsubstituted, linear, branched, or cyclicalkyl, alkenyl, or alkynyl; halogen, substituted or unsubstituted arylor heteroaryl, substituted or unsubstituted alkoxy; hydroxy, cyano,formyl, acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primaryamide (e.g., —CONH₂), secondary amide (e.g., —CONHR₁₂), tertiary amide(e.g., —CONR₁₂R₁₂), secondary carbamate (e.g., —OCONHR₁₂; —NHCOOR₁₂),tertiary carbamate (e.g., —OCONR₁₂R₁₂; —NR₁₂COOR₁₂), urea (e.g.,—NHCONHR₁₂; —NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂), carbinol (e.g.,—CH₂OH; —CHR₁₂OH, —CR₁₂R₁₂OH), ester (e.g., —COOR₁₂), thiol (—SH),primary amine (—NH₂), secondary amine (e.g., —NHR₁₂), tertiary amine(e.g., —NR₁₂R₁₂), thioether (e.g., —SR₁₂), sulfinyl group (e.g.,—SOR₁₂), sulfonyl group (e.g., —SOOR₁₂), provided that R₃ and R₈ aresubstituted alkoxy, such as —O(CH₂)_(m)X, where X is halogen or anaromatic or non-aromatic heterocyclic ring, such as

wherein

T is O, S, or NR₁₁, wherein each occurrence of R and R₁₁ is defined asabove form R₁-R₁₀;

n=0, 2, 3, or 4;

m is an integer from 0 -10; and

z, as valence permits, is an integer from 0-10.

The compound(s) can be formulated with one or more pharmaceuticallyacceptable carriers and/or excipients to prepare pharmaceuticalcompositions. The compositions can be formulated for enteral (e.g.,oral), parenteral (e.g., intravenous), topical, or transdermaladministration.

The compounds can be administered to treat a proliferative disease, suchas cancer. The compounds described herein showed significantcytotoxicity against cancer cells, such as human cervical cancer cells(HeLa)

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph showing the cytotoxicity (fraction of cellsurvival) of curcumin analogues in Hela cells using the MTT assay at 50μM. Data represent average values of three replicates.

FIG. 2 is a bar graph showing the cytotoxicity of curcumin analogues inHela cells using the MTT assay at 20 μM (red color bars) and 2 μM (bluecolor bars). Data represents average values of three replicates.

FIGS. 3A-D are dose response curves for doxorubicin and compounds 3a,3j, and 4e against Hela cells.

FIGS. 4A-D are dose response curves for doxorubicin and compounds 3a,4i, and 6g against HeK cells.

FIG. 5 is a bar graph showing the cytotoxicity (fraction of cellsurvival) of curcumin analogs SR11-17, SR35-40, and SR 43 in Hela cellsusing the MTT assay at 50 μM. Data represent average values of threereplicates.

FIGS. 6A-6C are line graphs comparing the activity of SM226 (FIG. A), SM229 (FIG. B), and SM 232 (FIG. C) with doxorubicin against MOLT 4 cellline as a function of drug concentration (micromolar).

FIGS. 7A-7C are line graphs comparing the activity of SM226 (FIG. A), SM229 (FIG. B), and SM 232 (FIG. C) with doxorubicin against HeLa cellline as a function of drug concentration (micromolar).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

An “effective amount”, e.g., of the compounds described herein, refersto an amount of the compound in a composition or formulation which, whenapplied as part of a desired dosage regimen brings about, e.g., a changein the rate of cell proliferation and/or the state of differentiation ofa cell and/or rate of survival of a cell according to clinicallyacceptable standards for the disorder to be treated.

The “growth state” of a cell refers to the rate of proliferation of thecell and/or the state of differentiation of the cell. An “altered growthstate” is a growth state characterized by an abnormal rate ofproliferation, e.g., a cell exhibiting an increased or decreased rate ofproliferation relative to a normal cell.

The term “patient” or “subject” to be treated refers to either a humanor non-human animal.

The term “prodrug”, as used herein, refers to compounds that, underphysiological conditions, are converted into the therapeutically activecompound described herein. A common method for making a prodrug is toinclude selected moieties, which are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

As used herein, “proliferating” and “proliferation” refer to cellsundergoing mitosis.

As generally used herein “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues, organs, and/or bodily fluids of human beings andanimals without excessive toxicity, irritation, allergic response, orother problems or complications commensurate with a reasonablebenefit/risk ratio.

“Stereoisomer”, as used herein, refers to isomeric molecules that havethe same molecular formula and sequence of bonded atoms (constitution),but which differ in the three dimensional orientations of their atoms inspace. Examples of stereoisomers include enantiomers and diastereomers.As used herein, an enantiomer refers to one of the two mirror-imageforms of an optically active or chiral molecule. Diastereomers (ordiastereoisomers) are stereoisomers that are not enantiomers(non-superimposable mirror images of each other). Chiral moleculescontain a chiral center, also referred to as a stereocenter orstereogenic center, which is any point, though not necessarily an atom,in a molecule bearing groups such that an interchanging of any twogroups leads to a stereoisomer. In organic compounds, the chiral centeris typically a carbon, phosphorus or sulfur atom, though it is alsopossible for other atoms to be stereocenters in organic and inorganiccompounds. A molecule can have multiple stereocenters, giving it manystereoisomers. In compounds whose stereoisomerism is due to tetrahedralstereogenic centers (e.g., tetrahedral carbon), the total number ofhypothetically possible stereoisomers will not exceed 2n, where n is thenumber of tetrahedral stereocenters. Molecules with symmetry frequentlyhave fewer than the maximum possible number of stereoisomers. A 50:50mixture of enantiomers is referred to as a racemic mixture.Alternatively, a mixture of enantiomers can be enantiomerically enrichedso that one enantiomer is present in an amount greater than 50%.Enantiomers and/or diasteromers can be resolved or separated usingtechniques known in the art.

“Half maximal inhibitory concentration, IC₅₀”, as used herein, refers toa measure of the effectiveness of a compound in inhibiting biological orbiochemical function. This quantitative measure indicates how much of aparticular drug or other substance (inhibitor) is needed to inhibit agiven biological process (or component of a process, i.e. an enzyme,cell, cell receptor or microorganism) by half. According to the FDA,IC₅₀ represents the concentration of a drug that is required for 50%inhibition in vitro. The IC₅₀ can be determined using a variety ofassays known in the art.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl(alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups.

In preferred embodiments, a straight chain or branched chain alkyl has30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straightchains, C₃-C₃₀ for branched chains), and more preferably 20 or fewer.Likewise, preferred cycloalkyls have from 3-10 carbon atoms in theirring structure, and more preferably have 5, 6 or 7 carbons in the ringstructure. The term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having one or more substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone. Suchsubstituents include, but are not limited to, halogen, hydroxyl,carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl),thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amino,amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate,sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, oran aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Throughout the application, preferred alkylgroups are lower alkyls. In preferred embodiments, a substituentdesignated herein as alkyl is a lower alkyl.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude halogen, hydroxy, nitro, thiols, amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, aswell as ethers, alkylthios, carbonyls (including ketones, aldehydes,carboxylates, and esters), —CF₃, —CN and the like. Cycloalkyls can besubstituted in the same manner.

The term “heteroalkyl”, as used herein, refers to straight or branchedchain, or cyclic carbon-containing radicals, or combinations thereof,containing at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, and—S-alkynyl. Representative alkylthio groups include methylthio,ethylthio, and the like. The term “alkylthio” also encompassescycloalkyl groups, alkene and cycloalkene groups, and alkyne groups.“Arylthio” refers to aryl or heteroaryl groups.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The terms “alkoxyl” or “alkoxy” as used herein refer to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, and —O-alkynyl. Aroxy can berepresented by —O-aryl or O-heteroaryl, wherein aryl and heteroaryl areas defined below. The alkoxy and phenoxyl groups can be substituted asdescribed above for alkyl.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

wherein, R₉, R₁₀, and R′₁₀ each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R₈ or R₉ and R₁₀ taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R₈ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In preferred embodiments, only one of R₉ or R₁₀can be a carbonyl, e.g., R₉, R₁₀ and the nitrogen together do not forman imide. In still more preferred embodiments, the term “amine” does notencompass amides, e.g., wherein one of R₉ and R₁₀ represents a carbonyl.In even more preferred embodiments, R₉ and R₁₀ (and optionally R′₁₀)each independently represent a hydrogen, an alkyl or cycloalkyl, analkenyl or cycloalkenyl, or alkynyl.

Thus, the term “alkylamine” as used herein means an amine group, asdefined above, having a substituted (as described above for alkyl) orunsubstituted alkyl attached thereto, i.e., at least one of R₉ and R₁₀is an alkyl group.

The term “amide” is art-recognized as an amino-substituted carbonyl andincludes a moiety that can be represented by the general formula:

wherein, R₉ and R₁₀ are as defined above.

“Aryl”, as used herein, refers to C₅-C₁₀-membered aromatic,heterocyclic, fused aromatic, fused heterocyclic, biaromatic, orbihetereocyclic ring systems. Broadly defined, “aryl”, as used herein,includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groupsthat may include from zero to four heteroatoms, for example, benzene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics”. The aromaticring can be substituted at one or more ring positions with one or moresubstituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (orquaternized amino), nitro, sulthydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN; and combinations thereof.

The term “aryl” also includes polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoiningrings (i.e., “fused rings”) wherein at least one of the rings isaromatic, e.g., the other cyclic ring or rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. Examples ofheterocyclic rings include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, (uranyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or moreof the rings can be substituted as defined above for “aryl”.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group).

The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

“Heterocycle” or “heterocyclic”, as used herein, refers to a cyclicradical attached via a ring carbon or nitrogen of a monocyclic orbicyclic ring containing 3-10 ring atoms, and preferably from 5-6 ringatoms, consisting of carbon and one to four heteroatoms each selectedfrom the group consisting of non-peroxide oxygen, sulfur, and N(Y)wherein Y is absent or is H, O, (C₁-C₁₀) alkyl, phenyl or benzyl, andoptionally containing 1-3 double bonds and optionally substituted withone or more substituents. Examples of heterocyclic ring include, but arenot limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, ehromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. Heterocyclicgroups can optionally be substituted with one or more substituents atone or more positions as defined above for alkyl and aryl, for example,halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino,nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF3, —CN,or the like.

The term “carbonyl” is art-recognized and includes such moieties as canbe represented by the general formula:

wherein, X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, ancycloalkenyl, or an alkynyl, R′₁₁ represents a hydrogen, an alkyl, acycloalkyl, an alkenyl, an cycloalkenyl, or an alkynyl. Where X is anoxygen and R₁₁ or R′₁₁ is not hydrogen, the formula represents an“ester”. Where X is an oxygen and R₁₁ is as defined above, the moiety isreferred to herein as a carboxyl group, and particularly when R₁₁ is ahydrogen, the formula represents a “carboxylic acid”. Where X is anoxygen and is hydrogen, the formula represents a “formate”. In general,where the oxygen atom of the above formula is replaced by sulfur, theformula represents a “thiocarbonyl” group. Where X is a sulfur and R₁₁or R′₁₁ is not hydrogen; the formula represents a “thioester.” Where Xis a sulfur and R₁₁ is hydrogen, the formula represents a“thiocarboxylic acid.” Where X is a sulfur and R′₁₁ is hydrogen, theformula represents a “thiofoxmate.” On the other hand, where X is abond, and R₁₁ is not hydrogen, the above formula represents a “ketone”group. Where X is a bond, and R₁₁ is hydrogen, the above formularepresents an “aldehyde” group.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are boron, nitrogen,oxygen, phosphorus, sulfur and selenium. Other heteroatoms includesilicon and arsenic.

As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sullhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

“Linker” or “spacer”, as used herein, refers to an atom or atoms thatseparate the 6-membered ring of the curcuminoid from the substituentR₁₁. The Linker or spacer can be a single atom, such as a heteroatom(e.g., O or S), a group of atoms, such as a functional group (e.g.,amine, —C(═O)—, —CH₂—), or multiple groups of atoms, such as an alkylenechain.

The term “substituted” as used herein, refers to all permissiblesubstituents of the compounds described herein. In the broadest sense,the permissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,but are not limited to, halogens, hydroxyl groups, or any other organicgroupings containing any number of carbon atoms, preferably 1-14 carbonatoms, and optionally include one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats. Representative substituents include alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl,substituted phenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy,substituted phenoxy, aroxy, substituted aroxy, alkylthio, substitutedalkylthio, phenylthio, substituted phenylthio, arylthio, substitutedarylthio, cyano, isocyano, substituted isocyano, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, andpolypeptide groups.

Heteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valences of the heteroatoms. It is understood that“substitution” or “substituted” includes the implicit proviso that suchsubstitution is in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound, i.e. a compound that does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

II. Compounds

1. Curcuminoids

The compounds described herein are compounds of Formula I:

wherein R₁-R₁₀ are independently absent or selected from the groupconsisting of substituted or unsubstituted, linear, branched, or cyclicalkyl, alkenyl, or alkynyl; halogen, substituted or unsubstituted arylor heteroaryl; substituted or unsubstituted alkoxy; hydroxy, cyano,formyl, acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primaryamide (e.g., —CONH₂), secondary amide (e.g., —CONHR₁₂), tertiary amide(e.g., —CONR₁₂R₁₂), secondary carbamate (e.g., —CONHR₁₂; —NHCOOR₁₂),tertiary carbamate (e.g., —OCONR₁₂R₁₂; —NR₁₂COOR₁₂), urea (e.g.,—NHCONHR₁₂; —NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂), carbinol (e.g.,—CH₂OH; —CHR₁₂OH, —CR₁₂R₁₂OH), ester (e.g., —COOR₁₂), thiol (—SH),primary amine (—NH₂), secondary amine (e.g., —NHR₁₂), tertiary amine(e.g., —NR₁₂R₁₂), thioether (e.g., —SR₁₂), sulfinyl group (e.g.,—SOR₁₂), sulfonyl group (e.g., —SOOR₁₂);

R₁₁ is substituted or unsubstituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, or alkynyl; substituted or unsubstituted benzyl sulfonyl(Bnz); substituted or substituted p-toluene sulfonyl (p-Ts); substitutedor unsubstituted benzyl; substituted or unsubstituted aryl; substitutedor unsubstituted heteroaryl; wherein the R₁₁ if substituted, can besubstituted with one or more of alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkoxy, amine, halogen, hydroxyl, nitrile, CF₃, ester,amide, urea, carbamate, thioether, carboxylic acid, and aryl; and

L is absent or a linker or spacer.

In some embodiments, R₁₁ is unsubstituted alkyl, such as methyl, ethyl,or propyl. In some embodiments, R₁₁ is unsubstituted ethyl. In someembodiments, R₁₁ is unsubstituted ethyl and at least one of R₁-R₅ and atleast one of R₆-R₁₀ are halogen (e.g., Br, Cl, or F). In particularembodiments, R₁₁ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, and R₁₀ arehydrogen. In more particular embodiments, R₃ and R₈ are the samehalogen. In still other embodiments, R₁₁ is unsubstituted ethyl and atleast one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstituted alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. Inparticular embodiments, R₃ and R₈ are unsubstituted alkyl and R₁, R₂,R₄-R₇, R₉, and R₁₀ are hydrogen. In more particular embodiments, R₃ andR₈ are the same unsubstituted alkyl. In still other embodiments, R₁₁ isunsubstituted ethyl and at least one of R₁-R₅ and at least one of R₆-R₁₀are unsubstituted alkoxy, such as methoxy. In particular embodiments, R₃and R₈ are unsubstituted alkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ arehydrogen. In more particular embodiments, R₃ and R₈ are the sameunsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted p-toluene sulfonyl. In someembodiments, R₁₁ is unsubstituted p-toluene sulfonyl and at least one ofR₁-R₅ and at least one of R₆-R₁₀ are halogen (e.g., Br, Cl, or F). Inparticular embodiments, R₃ and R₈ are halogen and R_(I), R₂, R₄-R₇, R₉,and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are thesame halogen. In still other embodiments, R₁₁ is unsubstituted p-toluenesulfonyl and at least one of R₁-R₅ and at least one of R₆-R₁₀ areunsubstituted alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, or t-butyl. In particular embodiments, R₃ and R₈ areunsubstituted alkyl and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In moreparticular embodiments, R₃ and R₈ are the same unsubstituted alkyl. Instill other embodiments, R₁₁ is unsubstituted p-toluene sulfonyl and atleast one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstituted alkoxy,such as methoxy. In particular embodiments, R₃ and R₈ are unsubstitutedalkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In more particularembodiments, R₃ and R₈ are the same unsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted benzyl. In some embodiments,R₁₁ is unsubstituted benzyl and at least one of R₁-R₅ and at least oneof R₆-R₁₀ are halogen (e.g., Br, Cl, or F). In particular embodiments,R₃ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. Inmore particular embodiments, R₃ and R₈ are the same halogen. In stillother embodiments, R₁₁ is unsubstituted benzyl and at least one of R₁-R₅and at least one of R₆-R₁₀ are unsubstituted alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In particularembodiments, R₃ and R₈ are unsubstituted alkyl and R₁, R₂, R₄-R₇, R₉,and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are thesame unsubstituted alkyl. In still other embodiments, R₁₁ isunsubstituted benzyl and at least one of R₁-R₅ and at least one ofR₆-R₁₀ are unsubstituted alkoxy, such as methoxy. In particularembodiments, R₃ and R₈ are unsubstituted alkoxy and R₁, R₂, R₄-R₇, R₉,and R₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are thesame unsubstituted alkoxy.

In other embodiments, R₁₁ is unsubstituted benzyl sulfonyl. In someembodiments, R₁₁ is unsubstituted benzyl sulfonyl, at least one of R₁-R₅and at least one of R₆-R₁₀ are halogen (e.g., Br, Cl, or F). Inparticular embodiments, R₃ and R₈ are halogen and R₁, R₂, R₄-R₇, R₉, andR₁₀ are hydrogen. In more particular embodiments, R₃ and R₈ are the samehalogen. In still other embodiments, R₁₁ is unsubstituted benzylsulfonyl and at least one of R₁-R₅ and at least one of R₆-R₁₀ areunsubstituted alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, or t-butyl. In particular embodiments, R₃ and R₈ areunsubstituted alkyl and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In moreparticular embodiments, R₃ and R_(s) are the same unsubstituted alkyl.In still other embodiments, R₁₁ is unsubstituted benzyl sulfonyl and atleast one of R₁-R₅ and at least one of R₆-R₁₀ are unsubstituted alkoxy,such as methoxy. In particular embodiments, R₃ and R₈ are unsubstitutedalkoxy and R₁, R₂, R₄-R₇, R₉, and R₁₀ are hydrogen. In more particularembodiments, R₃ and R₈ are the same unsubstituted alkoxy.

In some embodiments, R₁-R₁₁ are as defined above and L is absent. Inother embodiments, L is a one-carbon spacer and R₁-R₁₁ are as definedabove.

In still other embodiments, L is present and R₁₁ is a substituted orunsubstituted aryl or heteroaryl group. In particular embodiments, L isa substituted or unsubstituted alkylene group, such as a methylenegroup, and R₁₁ is a substituted or unsubstituted triazole. In someembodiments, L is an alkylene groups, such as substituted orunsubstituted methylene linker and R₁₁ is a triazole group, such as

wherein L is attached to the triazole group at the C5 position. In someembodiments, the triazole ring is substituted at the nitrogen as shownabove. In particular embodiments, the triazole ring is substituted witha substituted alkyl group. In more particular embodiments, the alkylgroup is substituted as shown below:

Compounds which were synthesized and evaluated for cytotoxicity areshown in Table 1.

TABLE 1 Synthesized compounds Molecular Mol. Code Structure Formula Wt.3a

C₂₆H₂₁Br₂NO₃S 587.32 3b

C₃₀H₃₁NO₃S 485.63 3c

C₃₂H₃₅NO₃S 513.69 3d

C₂₈H₂₇NO₃S 457.58 3e

C₂₆H₂₁Cl₂NO₃S 498.42 3f

C₂₈H₂₇NO₅S 489.58 3g

C₃₄H₃₉NO₃S 541.74 3h

C₃₄H₃₉NO₃S 541.74 3i

C₃₂H₃₅NO₃S 513.69 3j

C₂₆H₂₁F₂NO₃S 465.51 4a

C₂₇H₂₅NO₃S 443.55 4b

C₂₉H₂₉NO₃S 471.61 4c

C₃₁H₃₃NO₃S 499.66 4d

C₃₁H₃₃NO₃S 499.66 4e

C₂₅H₁₉Cl₂NO₃S 484.39 4f

C₃₃H₃₇NO₃S 527.71 4g

C₃₃H₃₇NO₃S 527.71 4h

C₂₇H₂₅NO₅S 475.55 4i

C₂₅H₁₉Br₂NO₃S 573.29 4j

C₂₅H₁₉F₂NO₃S 451.48 5a

C₂₈H₂₇NO 393.52 5b

C₂₆H₂₁Br₂NO 523.25 5c

C₃₀H₃₁NO 421.57 5d

C₃₂H₃₅NO 449.62 5e

C₃₂H₃₅NO 449.62 5f

C₃₄H₃₉NO 477.67 5g

C₃₄H₃₉NO 477.67 5h

C₂₈H₂₇NO₃ 425.51 5i

C₂₆H₂₁Cl₂NO 343.35 5j

C₂₆H₂₁F₂NO 401.44 6a

C₂₁H₁₉Br₂NO 461.18 6b

C₂₁H₁₉Cl₂NO 372.28 6c

C₂₁H₁₉F₂NO 339.37 6d

C₂₃H₂₅NO 331.45 6e

C₂₅H₂₉NO 359.5 6f

C₂₇H₃₃NO 387.55 6g

C₂₇H₃₃NO 387.55 6h

C₂₉H₃₇NO 415.61 6i

C₂₉H₃₇NO 415.61 6j

C₂₃H₂₅NO₃ 363.44

In other embodiments, L is an alkylene groups, such as substituted orunsubstituted methylene linker and R₁₁ is a triazole group, such as

wherein L is attached to the triazole group at the C5 position. In someembodiments, the triazole ring is substituted at the nitrogen as shownabove. In particular embodiments, the triazole ring is substituted witha substituted alkyl group. In more particular embodiments, the alkylgroup is substituted as shown below:

Examples of these compounds which were synthesized and evaluated forcytotoxicity are shown below in Table 2:

TABLE 2

SR-11

SR-12

SR-13

SR-14

SR-15

SR-16

SR-17

SR-34

SR-35

SR36

SR37

SR38

SR39

SR40

C5-curcuminoid-triazole conjugates (SR11-SR17, SR34-SR40) were alsoevaluated against HeLa cells. As shown in the examples, most of thesecompounds showed good activity against four cell lines (HeLa, PC3, DU145and KB).

In other embodiments, the compound has the formula:

wherein R₁-R₁₀ are independently absent or selected from the groupconsisting of substituted or unsubstituted, linear, branched, or cyclicalkyl, alkenyl, or alkynyl; halogen, substituted or unsubstituted arylor heteroaryl, substituted or unsubstituted alkoxy; hydroxy, cyano,formyl, acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primaryamide (e.g., —CONH₂), secondary amide (e.g., —CONHR₁₂), tertiary amide(e.g., —CONR₁₂R₁₂), secondary carbamate (e.g., —OCONHR₁₂; —NHCOOR₁₂),tertiary carbamate (e.g., —OCONR₁₂R₁₂; —NR₁₂COOR₁₂), urea (e.g.,—NHCONHR₁₂; —NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂), carbinol (e.g.,—CH₂OH; —CHR₁₂OH, —CR₁₂R₁₂OH), ester (e.g., —COOR₁₂), thiol (—SH),primary amine (—NH₂), secondary amine (e.g., —NHR₁₂), tertiary amine(e.g., —NR₁₂R₁₂), thioether (e.g., —SR₁₂), sulfinyl group (e.g.,—SOR₁₂), and sulfonyl group (e.g., —SOOR₁₂), provided that R₃ and R₈ aresubstituted alkoxy, such as —O(CH₂)_(m)X, where X is halogen or anaromatic or non-aromatic heterocyclic ring, such as

wherein

T is O, S, or NR₁₁, wherein each occurrence of R and R₁₁ is defined asabove form R₁-R₁₀;

n 0, 2, 3, or 4;

m is an integer from 0 -10; and

z, as valence permits, is an integer from 0-10.

In particular embodiments, n is 2 or 3; R₁ is —O(CH₂)₃X, wherein X ishalogen or a heterocyclic ring as described above.

In other embodiments, n is 2 or 3; R₁ is —O(CH₂)₃X, wherein X is halogenor a heterocyclic ring as described above; and R₂ and R₉ are other thanhydrogen. In particular embodiments, R₂ and R₉ are lower alkoxy, such asmethoxy.

Exemplary compounds include the following, which were tested in MOLT4and Hela cell.

TABLE 3 IC₅₀ (μM) IC₅₀ (μM) against against Molt4 Structure Hela cellcell

No activity below 2.5 μM >50 SM216

No activity below 2.5 μM No activity below 2.5 μM SM218

No activity below 2.5 μM No activity below 2.5 μM SM223

0.02 0.4 SM226

0.03 0.5 SM229

0.1  0.9 SM232

2. Curcumin Analogue Conjugates

The compounds described herein may be linked to another molecule ormolecules in order to improve the efficacy of the compounds. Suitablemolecules include, but are not limited to, targeting agents and agents,which increase the in vivo half-life of the compounds (e.g.,polyethylene glycol). The compounds can be linked to such molecules inany manner provided that each region of the conjugate continues toperform its intended function without significant impairment ofbiological activity, for example, the anti-tumor activity and/oranti-inflammatory activity of the compounds disclosed herein.

The compounds described herein may be directly linked to a secondcompound or may be linked via a linker. The term “linker”, as usedherein, refers to one or more polyfunctional, e.g., bifunctionalmolecules, which can be used to covalently couple the one or morecompounds to the molecule(s) and which do not interfere with thebiological activity of the compounds. The linker may be attached to anypart of the compounds so long as the point of attachment does notinterfere with the biological activity, for example, the anti-tumorand/or anti-inflammatory activity of the compounds described herein.

In one embodiment, the compounds are conjugated to a second moleculethrough a reactive functional group on the compound, such as an ester,followed by reaction of the ester with a nucleophilic functional groupon the molecule to be linked. The esters may be prepared, for example,by reaction of a carboxyl group on the compound with an alcohol in thepresence of a dehydration agent such as dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or1-(3-dimethylamino propyl)-3-ethylcarbodiimide methiodide (EDCI). Theagent to be linked to the compound(s), for example, a tumor-specificantibody, is then mixed with the activated ester in aqueous solution toform the conjugate.

Alternatively, the ester of the compounds(s) may be prepared asdescribed above and reacted with a linker group, for example,2-aminoethanol, an alkylene diamine, an amino acid such as glycine, or acarboxy-protected amino acid such as glycine tert-butyl ester. If thelinker contains a protected carboxy group, the protecting group isremoved and the ester of the linker is prepared (as described above).The active ester is then reacted with the second molecule to give theconjugate. In another embodiment, the second agent can be derivatizedwith succinic anhydride to give an agent-succinate conjugate, which maybe condensed in the presence of EDC or EDCI with a linker having a freeamino or hydroxyl group.

It also is possible to prepare a compound containing a linker with afree amino group and crosslink the free amino group with aheterobifunctional cross linker such as sulfosuccinimidyl4-(N-maleimidocyclohexane)-1-carboxylate which will react with the freesulfhydryl groups of protein antigens.

The compounds may also be coupled to a linker by reaction of thealdehyde group with an amino linker to form an intermediate imineconjugate, followed by reduction with sodium borohydride or sodiumcyanoborohydride. Examples of such linkers include amino alcohols suchas 2-aminoethanol and diamino compounds such as ethylenediamine,1,2-propylenediamine, 1,5-pentanediamine, 1,6-hexanediamine, and thelike. The compounds may then be coupled to the linker by first formingthe succinated derivative with succinic anhydride followed bycondensation with the linker with DCC, EDC.

In addition, the compounds may be oxidized with periodate and theresulting dialdehyde condensed with an amino alcohol or diamino compoundlisted above. The free hydroxyl or amino group on the linker may then becondensed with the succinate derivative of the antigen in the presenceof DCC, EDC or EDCI. Many types of linkers are known in the art and maybe used in the creation of conjugates. A non-limiting list of exemplarylinkers is shown in Table 4.

TABLE 4 Examples of hetero-bifunctional cross-linking agentsHetero-Bifunctional Cross Linking Agents Spacer Arm Length afterReactive Advantages and crosslinking Linker Toward Applications(angstroms) SMPT Primary amines Greater stability 11.2 Sulfhydryls SPDPPrimary amines Thiolation Cleav- 6.8 Sulfhydryls able cross-linkingLC-SPDP Primary amines Extended spacer 15.6 Sulfhydryls arm Sulfo-LC-Primary amines Extended spacer 15.6 SPDP Sulfhydryls arm Water solubleSMCC Primary amines Stable maleimide 11.6 Sulfhydryls reactive groupEnzyme-antibody conjugation Hapten-carrier protein conjugation Sulfo-Primary amines Stable maleimide 11.6 SMCC Sulfhydryls reactive groupEnzyme-antibody conjugation MBS Primary amines Enzyme-antibody 9.9Sulfhydryls conjugation Hapten-carrier protein conjugation Sulfo-MBSPrimary amines Water soluble 9.9 Sulfhydryls SIAB Primary aminesEnzyme-antibody 10.6 Sulfhydryls conjugation Sulfo-SIAB Primary aminesWater soluble 10.6 Sulfhydryls SMPB Primary amines Extended spacer 14.5Sulfhydryls arm Enzyme-antibody conjugation Sulfo-SMPB Primary aminesExtended spacer 14.5 Sulfhydryls arm Water-soluble EDC/Sulfo- Primaryamines Hapten-carrier 0 NHS Carboxyl groups conjugation ABHCarbohydrates Reacts with sugar 11.9 Non-selective moieties

III. Pharmaceutical Compositions

The compounds described herein can be formulated for enteral,parenteral, topical, or pulmonary administration. The compounds can becombined with one or more pharmaceutically acceptable carriers and/orexcipients that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. The carrier is all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients.

A. Parenteral Formulations

The compounds described herein can be formulated for parenteraladministration. “Parenteral administration”, as used herein, meansadministration by any method other than through the digestive tract ornon-invasive topical or regional routes. For example, parenteraladministration may include administration to a patient intravenously,intradermally, intraarterially, intraperitoneally, intralesionally,intracranially, intraarticularly, intraprostatically, intrapleurally,intratracheally, intravitreally, intratumorally, intramuscularly,subcutaneously, subconjunctivally, intravesicularly, intrapericardially,intraumbilically, by injection, and by infusion.

Parenteral formulations can be prepared as aqueous compositions usingtechniques is known in the art. Typically, such compositions can beprepared as injectable formulations, for example, solutions orsuspensions; solid forms suitable for using to prepare solutions orsuspensions upon the addition of a reconstitution medium prior toinjection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water(o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.

The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, one or more polyols (e.g., glycerol, propyleneglycol, and liquid polyethylene glycol), oils, such as vegetable oils(e.g., peanut oil, corn oil, sesame oil, etc.), and combinationsthereof. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and/or by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride.

Solutions and dispersions of the active compounds as the free acid orbase or pharmacologically acceptable salts thereof can be prepared inwater or another solvent or dispersing medium suitably mixed with one ormore pharmaceutically acceptable excipients including, but not limitedto, surfactants, dispersants, emulsifiers, pH modifying agents,viscosity modifying agents, and combination thereof.

Suitable surfactants may be anionic, cationic, amphoteric or nonionicsurface-active agents. Suitable anionic surfactants include, but are notlimited to, those containing carboxylate, sulfonate and sulfate ions.Examples of anionic surfactants include sodium, potassium, ammonium oflong chain alkyl sulfonates and alkyl aryl sulfonates such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. Cationic surfactants include, but are not limited to,quaternary ammonium compounds such as benzalkonium chloride,benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples ofnonionic surfactants include ethylene glycol monostearate, propyleneglycol myristate, glyceryl monostearate, glyceryl stearate,polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates,polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylenetridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401,stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodiumN-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

The formulation can contain a preservative to prevent the growth ofmicroorganisms. Suitable preservatives include, but are not limited to,parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. Theformulation may also contain an antioxidant to prevent degradation ofthe active agent(s).

The formulation is typically buffered to a pH of 3-8 for parenteraladministration upon reconstitution. Suitable buffers include, but arenot limited to, phosphate buffers, acetate buffers, and citrate buffers.

Water-soluble polymers are often used in formulations for parenteraladministration. Suitable water-soluble polymers include, but are notlimited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, andpolyethylene glycol.

Sterile injectable solutions can be prepared by incorporating the activecompounds in the required amount in the appropriate solvent ordispersion medium with one or more of the excipients listed above, asrequired, followed by filtered sterilization. Generally, dispersions areprepared by incorporating the various sterilized active ingredients intoa sterile vehicle which contains the basic dispersion medium and therequired other ingredients from those listed above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. The powders can be prepared in such a manner that theparticles are porous in nature, which can increase dissolution of theparticles. Methods for making porous particles are well known in theart.

1. Controlled Release Formulations

The parenteral formulations described herein can be formulated forcontrolled release including immediate release, delayed release,extended release, pulsatile release, and combinations thereof.

i. Nano- and Microparticles

For parenteral administration, the one or more compounds, and optionalone or more additional active agents, can be incorporated intomicroparticles, nanoparticles, or combinations thereof that providecontrolled release of the compounds and/or one or more additional activeagents. In embodiments wherein the formulations contains two or moredrugs, the drugs can be formulated for the same type of controlledrelease (e.g., delayed, extended, immediate, or pulsatile) or the drugscan be independently formulated for different types of release (e.g.,immediate and delayed, immediate and extended, delayed and extended,delayed and pulsatile, etc.).

For example, the compounds and/or one or more additional active agentscan be incorporated into polymeric microparticles, which providecontrolled release of the drug(s). Release of the drug(s) is controlledby diffusion of the drug(s) out of the microparticles and/or degradationof the polymeric particles by hydrolysis and/or enzymatic degradation.Suitable polymers include ethylcellulose and other natural or syntheticcellulose derivatives.

Polymers, which are slowly soluble and form a gel in an aqueousenvironment, such as hydroxypropyl methylcellulose or polyethyleneoxide, may also be suitable as materials for drug containingmicroparticles. Other polymers include, but are not limited to,polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such aspolylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide)(PLGA), poly-3-hydroxybutyrate (PHB) and copolymers thereof,poly-4-hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactoneand copolymers thereof, and combinations thereof.

Alternatively, the drug(s) can be incorporated into microparticlesprepared from materials which are insoluble in aqueous solution orslowly soluble in aqueous solution, but are capable of degrading withinthe GI tract by means including enzymatic degradation, surfactant actionof bile acids, and/or mechanical erosion. As used herein, the term“slowly soluble in water” refers to materials that are not dissolved inwater within a period of 30 minutes. Preferred examples include fats,fatty substances, waxes, wax-like substances and mixtures thereof.Suitable fats and fatty substances include fatty alcohols (such aslauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty acids andderivatives, including but not limited to fatty acid esters, fatty acidglycerides (mono-, di- and tri-glycerides), and hydrogenated fats.Specific examples include, but are not limited to hydrogenated vegetableoil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenatedoils available under the trade name Sterotex®, stearic acid, cocoabutter, and stearyl alcohol. Suitable waxes and wax-like materialsinclude natural or synthetic waxes, hydrocarbons, and normal waxes.Specific examples of waxes include beeswax, glycowax, castor wax,carnauba wax, paraffins and candelilla wax. As used herein, a wax-likematerial is defined as any material, which is normally solid at roomtemperature and has a melting point of from about 30 to 300° C.

In some cases, it may be desirable to alter the rate of waterpenetration into the microparticles. To this end, rate-controlling(wicking) agents may be formulated along with the fats or waxes listedabove. Examples of rate-controlling materials include certain starchderivatives (e.g., waxy maltodextrin and drum dried corn starch),cellulose derivatives (e.g., hydroxypropylmethyl-cellulose,hydroxypropylcellulose, methylcellulose, and carboxymethyl-cellulose),alginic acid, lactose and talc. Additionally, a pharmaceuticallyacceptable surfactant (for example, lecithin) may be added to facilitatethe degradation of such microparticles.

Proteins, which are water insoluble, such as zein, can also be used asmaterials for the formation of drug containing microparticles.Additionally, proteins, polysaccharides and combinations thereof, whichare water-soluble, can be formulated with drug into microparticles andsubsequently cross-linked to form an insoluble network. For example,cyclodextrins can be complexed with individual drug molecules andsubsequently cross-linked.

Encapsulation or incorporation of drug into carrier materials to producedrug-containing microparticles can be achieved through knownpharmaceutical formulation techniques. In the case of formulation infats, waxes or wax-like materials, the carrier material is typicallyheated above its melting temperature and the drug is added to form amixture comprising drug particles suspended in the carrier material,drug dissolved in the carrier material, or a mixture thereof.Microparticles can be subsequently formulated through several methodsincluding, but not limited to, the processes of congealing, extrusion,spray chilling or aqueous dispersion. In a preferred process, wax isheated above its melting temperature, drug is added, and the moltenwax-drug mixture is congealed under constant stirring as the mixturecools. Alternatively, the molten wax-drug mixture can be extruded andspheronized to form pellets or beads. These processes are known in theart.

For some carrier materials it may be desirable to use a solventevaporation technique to produce drug-containing microparticles. In thiscase drug and carrier material are co-dissolved in a mutual solvent andmicroparticles can subsequently be produced by several techniquesincluding, but not limited to, forming an emulsion in water or otherappropriate media, spray drying or by evaporating off the solvent fromthe bulk solution and milling the resulting material.

In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, the drugpowder itself may be milled to generate fine particles prior toformulation. The process of jet milling, known in the pharmaceuticalart, can be used for this purpose. In some embodiments drug in aparticulate form is homogeneously dispersed in a wax or wax likesubstance by heating the wax or wax like substance above its meltingpoint and adding the drug particles while stirring the mixture. In thiscase a pharmaceutically acceptable surfactant may be added to themixture to facilitate the dispersion of the drug particles.

The particles can also be coated with one or more modified releasecoatings. Solid esters of fatty acids, which are hydrolyzed by lipases,can be spray coated onto microparticles or drug particles. Zein is anexample of a naturally water-insoluble protein. It can be coated ontodrug containing microparticles or drug particles by spray coating or bywet granulation techniques. In addition to naturally water-insolublematerials, some substrates of digestive enzymes can be treated withcross-linking procedures, resulting in the formation of non-solublenetworks. Many methods of cross-linking proteins, initiated by bothchemical and physical means, have been reported. One of the most commonmethods to obtain cross-linking is the use of chemical cross-linkingagents. Examples of chemical cross-linking agents include aldehydes(gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, andgenipin. In addition to these cross-linking agents, oxidized and nativesugars have been used to cross-link gelatin. Cross-linking can also beaccomplished using enzymatic means; for example, transglutaminase hasbeen approved as a GRAS substance for cross-linking seafood products.Finally, cross-linking can be initiated by physical means such asthermal treatment, UV irradiation and gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water-soluble protein canbe spray coated onto the microparticles and subsequently cross-linked bythe one of the methods described above. Alternatively, drug-containingmicroparticles can be microencapsulated within protein bycoacervation-phase separation (for example, by the addition of salts)and subsequently cross-linked. Some suitable proteins for this purposeinclude gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished by reactionwith calcium salts or multivalent cations, which cross-link the mainpolymer chains. Pectin, alginate, dextran, amylose and guar gum aresubject to cross-linking in the presence of multivalent cations.Complexes between oppositely charged polysaccharides can also be formed;pectin and chitosan, for example, can be complexed via electrostaticinteractions.

In certain embodiments, it may be desirable to provide continuousdelivery of one or more compounds to a patient in need thereof. Forintravenous or intraarterial routes, this can be accomplished using dripsystems, such as by intravenous administration. For topicalapplications, repeated application can be done or a patch can be used toprovide continuous administration of the compounds over an extendedperiod of time.

2. Injectable/Implantable Solid Implants

The compounds described herein can be incorporated intoinjectable/implantable solid or semi-solid implants, such as polymericimplants. In one embodiment, the compounds are incorporated into apolymer that is a liquid or paste at room temperature, but upon contactwith aqueous medium, such as physiological fluids, exhibits an increasein viscosity to form a semi-solid or solid material. Exemplary polymersinclude, but are not limited to, hydroxyalkanoic acid polyesters derivedfrom the copolymerization of at least one unsaturated hydroxy fatty acidcopolymerized with hydroxyalkanoic acids. The polymer can be melted,mixed with the active substance and cast or injection molded into adevice. Such melt fabrication require polymers having a melting pointthat is below the temperature at which the substance to be delivered andpolymer degrade or become reactive. The device can also be prepared bysolvent casting where the polymer is dissolved in a solvent and the drugdissolved or dispersed in the polymer solution and the solvent is thenevaporated. Solvent processes require that the polymer be soluble inorganic solvents. Another method is compression molding of a mixedpowder of the polymer and the drug or polymer particles loaded with theactive agent.

Alternatively, the compounds can be incorporated into a polymer matrixand molded, compressed, or extruded into a device that is a solid atroom temperature. For example, the compounds can be incorporated into abiodegradable polymer, such as polyanhydrides, polyhydroalkanoic acids(MAO, PLA, PGA, PLGA, polycaprolactone, polyesters, polyamides,polyorthoesters, polyphosphazenes, proteins and polysaccharides such ascollagen, hyaluronic acid, albumin and gelatin, and combinations thereofand compressed into solid device, such as disks, or extruded into adevice, such as rods.

The release of the one or more compounds from the implant can be variedby selection of the polymer, the molecular weight of the polymer, and/irmodification of the polymer to increase degradation, such as thefounation of pores and/or incorporation of hydrolyzable linkages.Methods for modifying the properties of biodegradable polymers to varythe release profile of the compounds from the implant are well known inthe art.

B. Enteral Formulations

Suitable oral dosage forms include tablets, capsules, solutions,suspensions, syrups, and lozenges. Tablets can be made using compressionor molding techniques well known in the art. Gelatin or non-gelatincapsules can prepared as hard or soft capsule shells, which canencapsulate liquid, solid, and semi-solid fill materials, usingtechniques well known in the art.

Formulations may be prepared using a pharmaceutically acceptablecarrier. As generally used herein “carrier” includes, but is not limitedto, diluents, preservatives, binders, lubricants, disintegrators,swelling agents, fillers, stabilizers, and combinations thereof.

Carrier also includes all components of the coating composition, whichmay include plasticizers, pigments, colorants, stabilizing agents, andglidants. Delayed release dosage formulations may be prepared asdescribed in standard references. These references provide informationon carriers, materials, equipment and process for preparing tablets andcapsules and delayed release dosage forms of tablets, capsules, andgranules.

Examples of suitable coating materials include, but are not limited to,cellulose polymers such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate and hydroxypropyl methylcellulose acetate succinate; polyvinylacetate phthalate, acrylic acid polymers and copolymers, and methacrylicresins that are commercially available under the trade name EUDRAGIT®(Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carrierssuch as plasticizers, pigments, colorants, glidants, stabilizationagents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients include, but are notlimited to, diluents, binders, lubricants, disintegrants, colorants,stabilizers, and surfactants. Diluents, also referred to as “fillers,”are typically necessary to increase the bulk of a solid dosage form sothat a practical size is provided for compression of tablets orformation of beads and granules. Suitable diluents include, but are notlimited to, dicalcium phosphate dihydrate, calcium sulfate, lactose,sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose,kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinizedstarch, silicone dioxide, titanium oxide, magnesium aluminum silicateand powdered sugar.

Binders are used to impart cohesive qualities to a solid dosageformulation, and thus ensure that a tablet or bead or granule remainsintact after the formation of the dosage forms. Suitable bindermaterials include, but are not limited to, starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dextrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia, tragacanth, sodium alginate, cellulose, includinghydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, stearic acid, glycerol behenate, polyethylene glycol,talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or“breakup” after administration, and generally include, but are notlimited to, starch, sodium starch glycolate, sodium carboxymethylstarch, sodium carboxymethylcellulose, hydroxypropyl cellulose,pregelatinized starch, clays, cellulose, alginine, gums or cross linkedpolymers, such as cross-linked PVP (Polyplasdone® XL from GAF ChemicalCorp).

Stabilizers are used to inhibit or retard drug decomposition reactions,which include, by way of example, oxidative reactions. Suitablestabilizers include, but are not limited to, antioxidants, butylatedhydroxytoluene (BHT); ascorbic acid, its salts and esters; Vitamin E,tocopherol and its salts; sulfites such as sodium metabisulphite;cysteine and its derivatives; citric acid; propyl gallate, and butylatedhydroxyanisole (BHA).

i. Controlled Release Formulations

Oral dosage forms, such as capsules, tablets, solutions, andsuspensions, can for formulated for controlled release. For example, theone or more compounds and optional one or more additional active agentscan be formulated into nanoparticles, microparticles, and combinationsthereof, and encapsulated in a soft or hard gelatin or non-gelatincapsule or dispersed in a dispersing medium to form an oral suspensionor syrup. The particles can be formed of the drug and a controlledrelease polymer or matrix. Alternatively, the drug particles can becoated with one or more controlled release coatings prior toincorporation in to the finished dosage form.

In another embodiment, the one or more compounds and optional one ormore additional active agents are dispersed in a matrix material, whichgels or emulsifies upon contact with an aqueous medium, such asphysiological fluids. In the case of gels, the matrix swells entrappingthe active agents, which are released slowly over time by diffusionand/or degradation of the matrix material. Such matrices can beformulated as tablets or as fill materials for hard and soft capsules.

In still another embodiment, the one or more compounds, and optional oneor more additional active agents are formulated into a sold oral dosageform, such as a tablet or capsule, and the solid dosage form is coatedwith one or more controlled release coatings, such as a delayed releasecoatings or extended release coatings. The coating or coatings may alsocontain the compounds and/or additional active agents.

Extended Release Dosage Forms

The extended release formulations are generally prepared as diffusion orosmotic systems, which are known in the art. A diffusion systemtypically consists of two types of devices, a reservoir and a matrix,and is well known and described in the art. The matrix devices aregenerally prepared by compressing the drug with a slowly dissolvingpolymer carrier into a tablet form. The three major types of materialsused in the preparation of matrix devices are insoluble plastics,hydrophilic polymers, and fatty compounds. Plastic matrices include, butare not limited to, methyl acrylate-methyl methacrylate, polyvinylchloride, and polyethylene. Hydrophilic polymers include, but are notlimited to, cellulosic polymers such as methyl and ethyl cellulose,hydroxyalkylcelluloses such as hydroxypropyl-cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, andCarbopol® 934, polyethylene oxides and mixtures thereof. Fatty compoundsinclude, but are not limited to, various waxes such as carnauba wax andglyceryl tristearate and wax-type substances including hydrogenatedcastor oil or hydrogenated vegetable oil, or mixtures thereof.

In certain preferred embodiments, the plastic material is apharmaceutically acceptable acrylic polymer, including but not limitedto, acrylic acid and methacrylic acid copolymers, methyl methacrylate,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymerpoly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In one preferred embodiment, the acrylic polymer is an acrylic resinlacquer such as that which is commercially available from Rohm Pharmaunder the tradename Eudragit®. In further preferred embodiments, theacrylic polymer comprises a mixture of two acrylic resin lacquerscommercially available from Rohm Pharma under the tradenames Eudragit®RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit®RS30D are copolymers of acrylic and methacrylic esters with a lowcontent of quaternary ammonium groups, the molar ratio of ammoniumgroups to the remaining neutral (meth)acrylic esters being 1:20 inEudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecular weightis about 150,000. Edragit® S-100 and Eudragit® L-100 are also preferred.The code designations RL (high permeability) and RS (low permeability)refer to the permeability properties of these agents. Eudragit® RL/RSmixtures are insoluble in water and in digestive fluids.However,multiparticulate systems formed to include the same areswellable and permeable in aqueous solutions and digestive fluids.

The polymers described above such as Eudragit® RL/RS may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release multiparticulate systems may be obtained,for instance, from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit®RS, and 10% Eudragit® RL and 90% Eudragit® RS. One skilled in the artwill recognize that other acrylic polymers may also be used, such as,for example, Eudragit® L.

Alternatively, extended release formulations can be prepared usingosmotic systems or by applying a semi-permeable coating to the dosageform. In the latter case, the desired drug release profile can beachieved by combining low permeable and high permeable coating materialsin suitable proportion.

The devices with different drug release mechanisms described above canbe combined in a final dosage form comprising single or multiple units.Examples of multiple units include, but are not limited to, multilayertablets and capsules containing tablets, beads, or granules An immediaterelease portion can be added to the extended release system by means ofeither applying an immediate release layer on top of the extendedrelease core using a coating or compression process or in a multipleunit system such as a capsule containing extended and immediate releasebeads.

Extended release tablets containing hydrophilic polymers are prepared bytechniques commonly known in the art such as direct compression, wetgranulation, or dry granulation. Their formulations usually incorporatepolymers, diluents, binders, and lubricants as well as the activepharmaceutical ingredient. The usual diluents include inert powderedsubstances such as starches, powdered cellulose, especially crystallineand microcrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders. Typical diluentsinclude, for example, various types of starch, lactose, mannitol,kaolin, calcium phosphate or sulfate, inorganic salts such as sodiumchloride and powdered sugar. Powdered cellulose derivatives are alsouseful. Typical tablet binders include substances such as starch,gelatin and sugars such as lactose, fructose, and glucose. Natural andsynthetic gums, including acacia, alginates, methylcellulose, andpolyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilicpolymers, ethylcellulose and waxes can also serve as binders. Alubricant is necessary in a tablet formulation to prevent the tablet andpunches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Extended release tablets containing wax materials are generally preparedusing methods known in the art such as a direct blend method, acongealing method, and an aqueous dispersion method. In the congealingmethod, the drug is mixed with a wax material and either spray-congealedor congealed and screened and processed.

Delayed Release Dosage Forms

Delayed release formulations can be created by coating a solid dosageform with a polymer film, which is insoluble in the acidic environmentof the stomach, and soluble in the neutral environment of the smallintestine.

The delayed release dosage units can be prepared, for example, bycoating a drug or a drug-containing composition with a selected coatingmaterial. The drug-containing composition may be, e.g., a tablet forincorporation into a capsule, a tablet for use as an inner core in a“coated core” dosage form, or a plurality of drug-containing beads,particles or granules, for incorporation into either a tablet orcapsule. Preferred coating materials include bioerodible, graduallyhydrolyzable, gradually water-soluble, and/or enzymatically degradablepolymers, and may be conventional “enteric” polymers. Enteric polymers,as will be appreciated by those skilled in the art, become soluble inthe higher pH environment of the lower gastrointestinal tract or slowlyerode as the dosage form passes through the gastrointestinal tract,while enzymatically degradable polymers are degraded by bacterialenzymes present in the lower gastrointestinal tract, particularly in thecolon. Suitable coating materials for effecting delayed release include,but are not limited to, cellulosic polymers such as hydroxypropylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropylmethyl cellulose phthalate, methylcellulose,ethyl cellulose, cellulose acetate, cellulose acetate phthalate,cellulose acetate trimellitate and carboxymethylcellulose sodium;acrylic acid polymers and copolymers, preferably formed from acrylicacid, methacrylic acid, methyl acrylate, ethyl acrylate, methylmethacrylate and/or ethyl methacrylate, and other methacrylic resinsthat are commercially available under the tradename Eudragit® (RohmPharma; Westerstadt, Germany), including Eudragit® L30D-55 and L100-55(soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 andabove), Eudragit® S (soluble at pH 7.0 and above, as a result of ahigher degree of esterification), and Eudragits® NE, RL and RS(water-insoluble polymers having different degrees of permeability andexpandability); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene-vinyl acetate copolymer;enzymatically degradable polymers such as azo polymers, pectin,chitosan, amylose and guar gum; zein and shellac. Combinations ofdifferent coating materials may also be used. Multi-layer coatings usingdifferent polymers may also be applied.

The preferred coating weights for particular coating materials may bereadily determined by those skilled in the art by evaluating individualrelease profiles for tablets, beads and granules prepared with differentquantities of various coating materials. It is the combination ofmaterials, method and form of application that produce the desiredrelease characteristics, which one can determine only from the clinicalstudies.

The coating composition may include conventional additives, such asplasticizers, pigments, colorants, stabilizing agents, glidants, etc. Aplasticizer is normally present to reduce the fragility of the coating,and will generally represent about 10 wt. % to 50 wt. % relative to thedry weight of the polymer. Examples of typical plasticizers includepolyethylene glycol, propylene glycol, triacetin, dimethyl phthalate,diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethylcitrate, tributyl citrate, triethyl acetyl citrate, castor oil andacetylated monoglycerides. A stabilizing agent is preferably used tostabilize particles in the dispersion. Typical stabilizing agents arenonionic emulsifiers such as sorbitan esters, polysorbates andpolyvinylpyrrolidone. Glidants are recommended to reduce stickingeffects during film formation and drying, and will generally representapproximately 25 wt. % to 100 wt. % of the polymer weight in the coatingsolution. One effective glidant is talc. Other glidants such asmagnesium stearate and glycerol monostearates may also be used. Pigmentssuch as titanium dioxide may also be used. Small quantities of ananti-foaming agent, such as a silicone (e.g., simethicone), may also beadded to the coating composition.

C. Topical Formulations

Suitable dosage forms for topical administration include creams,ointments, salves, sprays, gels, lotions, emulsions, and transdermalpatches. The formulation may be formulated for transmucosal,transepithelial, transendothelial, or transdermal administration. Thecompounds can also be formulated for intranasal delivery, pulmonarydelivery, or inhalation. The compositions may further contain one ormore chemical penetration enhancers, membrane permeability agents,membrane transport agents, emollients, surfactants, stabilizers, andcombination thereof.

1. Topical Formulations

“Emollients” are an externally applied agent that softens or soothesskin and are generally known in the art and listed in compendia, such asthe “Handbook of Pharmaceutical Excipients”, 4^(th) Ed., PharmaceuticalPress, 2003. These include, without limitation, almond oil, castor oil,ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esterswax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycolpalmitostearate, glycerin, glycerin monostearate, glyceryl monooleate,isopropyl myristate, isopropyl palmitate, lanolin, lecithin, lightmineral oil, medium-chain triglycerides, mineral oil and lanolinalcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil,starch, stearyl alcohol, sunflower oil, xylitol and combinationsthereof. In one embodiment, the emollients are ethylhexylstearate andethylhexyl palmitate.

“Surfactants” are surface-active agents that lower surface tension andthereby increase the emulsifying, foaming, dispersing, spreading andwetting properties of a product. Suitable non-ionic surfactants includeemulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters,benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate,poloxamer, povidone and combinations thereof. In one embodiment, thenon-ionic surfactant is stearyl alcohol.

“Emulsifiers” are surface active substances which promote the suspensionof one liquid in another and promote the formation of a stable mixture,or emulsion, of oil and water. Common emulsifiers are: metallic soaps,certain animal and vegetable oils, and various polar compounds. Suitableemulsifiers include acacia, anionic emulsifying wax, calcium stearate,carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol,diethanolamine, ethylene glycol palmitostearate, glycerin monostearate,glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin,hydrous, lanolin alcohols, lecithin, medium-chain triglycerides,methylcellulose, mineral oil and lanolin alcohols, monobasic sodiumphosphate, monoethanolamine, nonionic emulsifying wax, oleic acid,poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylenecastor oil derivatives, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene stearates, propylene glycol alginate, self-emulsifyingglyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate,sorbitan esters, stearic acid, sunflower oil, tragacanth,triethanolamine, xanthan gum and combinations thereof. In oneembodiment, the emulsifier is glycerol stearate.

Suitable classes of penetration enhancers are known in the art andinclude, but are not limited to, fatty alcohols, fatty acid esters,fatty acids, fatty alcohol ethers, amino acids, phospholipids,lecithins, cholate salts, enzymes, amines and amides, complexing agents(liposomes, cyclodextrins, modified celluloses, and diimides),macrocyclics, such as macrocylic lactones, ketones, and anhydrides andcyclic ureas, surfactants, N-methyl pyrrolidones and derivativesthereof, DMSO and related compounds, ionic compounds, azone and relatedcompounds, and solvents, such as alcohols, ketones, amides, polyols(e.g., glycols). Examples of these classes are known in the art.

1. Lotions, Creams, Gels, Ointments, Emulsions, and Foams

“Hydrophilic” as used herein refers to substances that have stronglypolar groups that readily interact with water.

“Lipophilic” refers to compounds having an affinity for lipids.

“Amphiphilic” refers to a molecule combining hydrophilic and lipophilic(hydrophobic) properties

“Hydrophobic” as used herein refers to substances that lack an affinityfor water; tending to repel and not absorb water as well as not dissolvein or mix with water.

A “gel” is a colloid in which the dispersed phase has combined with thecontinuous phase to produce a semisolid material, such as jelly.

An “oil” is a composition containing at least 95% wt of a lipophilicsubstance. Examples of lipophilic substances include but are not limitedto naturally occurring and synthetic oils, fats, fatty acids, lecithins,triglycerides and combinations thereof.

A “continuous phase” refers to the liquid in which solids are suspendedor droplets of another liquid are dispersed, and is sometimes called theexternal phase. This also refers to the fluid phase of a colloid withinwhich solid or fluid particles are distributed. If the continuous phaseis water (or another hydrophilic solvent), water-soluble or hydrophilicdrugs will dissolve in the continuous phase (as opposed to beingdispersed). In a multiphase formulation (e.g., an emulsion), thediscreet phase is suspended or dispersed in the continuous phase.

An “emulsion” is a composition containing a mixture of non-misciblecomponents homogenously blended together. In particular embodiments, thenon-miscible components include a lipophilic component and an aqueouscomponent. An emulsion is a preparation of one liquid distributed insmall globules throughout the body of a second liquid. The dispersedliquid is the discontinuous phase, and the dispersion medium is thecontinuous phase. When oil is the dispersed liquid and an aqueoussolution is the continuous phase, it is known as an oil-in-wateremulsion, whereas when water or aqueous solution is the dispersed phaseand oil or oleaginous substance is the continuous phase, it is known asa water-in-oil emulsion. Either or both of the oil phase and the aqueousphase may contain one or more surfactants, emulsifiers, emulsionstabilizers, buffers, and other excipients. Preferred excipients includesurfactants, especially non-ionic surfactants; emulsifying agents,especially emulsifying waxes; and liquid non-volatile non-aqueousmaterials, particularly glycols such as propylene glycol. The oil phasemay contain other oily pharmaceutically approved excipients. Forexample, materials such as hydroxylated castor oil or sesame oil may beused in the oil phase as surfactants or emulsifiers.

An emulsion is a preparation of one liquid distributed in small globulesthroughout the body of a second liquid. The dispersed liquid is thediscontinuous phase, and the dispersion medium is the continuous phase.When oil is the dispersed liquid and an aqueous solution is thecontinuous phase, it is known as an oil-in-water emulsion, whereas whenwater or aqueous solution is the dispersed phase and oil or oleaginoussubstance is the continuous phase, it is known as a water-in-oilemulsion. The oil phase may consist at least in part of a propellant,such as an HFA propellant. Either or both of the oil phase and theaqueous phase may contain one or more surfactants, emulsifiers, emulsionstabilizers, buffers, and other excipients. Preferred excipients includesurfactants, especially non-ionic surfactants; emulsifying agents,especially emulsifying waxes; and liquid non-volatile non-aqueousmaterials, particularly glycols such as propylene glycol. The oil phasemay contain other oily pharmaceutically approved excipients. Forexample, materials such as hydroxylated castor oil or sesame oil may beused in the oil phase as surfactants or emulsifiers.

A sub-set of emulsions are the self-emulsifying systems. These drugdelivery systems are typically capsules (hard shell or soft shell)comprised of the drug dispersed or dissolved in a mixture ofsurfactant(s) and lipophilic liquids such as oils or other waterimmiscible liquids. When the capsule is exposed to an aqueousenvironment and the outer gelatin shell dissolves, contact between theaqueous medium and the capsule contents instantly generates very smallemulsion droplets. These typically are in the size range of micelles ornanoparticles. No mixing force is required to generate the emulsion asis typically the case in emulsion formulation processes.

A “lotion” is a low- to medium-viscosity liquid formulation. A lotioncan contain finely powdered substances that are in soluble in thedispersion medium through the use of suspending agents and dispersingagents. Alternatively, lotions can have as the dispersed phase liquidsubstances that are immiscible with the vehicle and are usuallydispersed by means of emulsifying agents or other suitable stabilizers.In one embodiment, the lotion is in the form of an emulsion having aviscosity of between 100 and 1000 centistokes. The fluidity of lotionspermits rapid and uniform application over a wide surface area. Lotionsare typically intended to dry on the skin leaving a thin coat of theirmedicinal components on the skin's surface.

A “cream” is a viscous liquid or semi-solid emulsion of either the“oil-in-water” or “water-in-oil type”. Creams may contain emulsifyingagents and/or other stabilizing agents. In one embodiment, theformulation is in the form of a cream having a viscosity of greater than1000 centistokes, typically in the range of 20,000-50,000 centistokes.Creams are often time preferred over ointments, as they are generallyeasier to spread and easier to remove.

The difference between a cream and a lotion is the viscosity, which isdependent on the amount use of various oils and the percentage of waterused to prepare the formulations. Creams are typically thicker thanlotions, may have various uses and often one uses more variedoils/butters, depending upon the desired effect upon the skin. In acream formulation, the water-base percentage is about 60-75% and theoil-base is about 20-30% of the total, with the other percentages beingthe emulsifier agent, preservatives and additives for a total of 100%.

An “ointment” is a semisolid preparation containing an ointment base andoptionally one or more active agents. Examples of suitable ointmentbases include hydrocarbon bases (e.g., petrolatum, white petrolatum,yellow ointment, and mineral oil); absorption bases (hydrophilicpetrolatum, anhydrous lanolin, lanolin, and cold cream); water-removablebases (e.g., hydrophilic ointment), and water-soluble bases (e.g.,polyethylene glycol ointments). Pastes typically differ from ointmentsin that they contain a larger percentage of solids. Pastes are typicallymore absorptive and less greasy that ointments prepared with the samecomponents.

A “gel” is a semisolid system containing dispersions of small or largemolecules in a liquid vehicle that is rendered semisolid by the actionof a thickening agent or polymeric material dissolved or suspended inthe liquid vehicle. The liquid may include a lipophilic component, anaqueous component or both. Some emulsions may be gels or otherwiseinclude a gel component. Some gels, however, are not emulsions becausethey do not contain a homogenized blend of immiscible components.Suitable gelling agents include, but are not limited to, modifiedcelluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose;Carbopol homopolymers and copolymers; and combinations thereof. Suitablesolvents in the liquid vehicle include, but are not limited to, diglycolmonoethyl ether; alklene glycols, such as propylene glycol; dimethylisosorbide; alcohols, such as isopropyl alcohol and ethanol. Thesolvents are typically selected for their ability to dissolve the drug.Other additives, which improve the skin feel and/or emolliency of theformulation, may also be incorporated. Examples of such additivesinclude, but are not limited, isopropyl myristate, ethyl acetate,C₁₂-C₁₅ alkyl benzoates, mineral oil, squalane, cyclomethicone,capric/caprylic triglycerides, and combinations thereof.

Foams consist of an emulsion in combination with a gaseous propellant.The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs).Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (FIFA 227), but mixtures andadmixtures of these and other HFAs that are currently approved or maybecome approved for medical use are suitable. The propellants preferablyare not hydrocarbon propellant gases, which can produce flammable orexplosive vapors during spraying. Furthermore, the compositionspreferably contain no volatile alcohols, which can produce flammable orexplosive vapors during use.

Buffers are used to control pH of a composition. Preferably, the buffersbuffer the composition from a pH of about 4 to a pH of about 7.5, morepreferably from a pH of about 4 to a pH of about 7, and most preferablyfrom a pH of about 5 to a pH of about 7. In a preferred embodiment, thebuffer is triethanolamine.

Preservatives can be used to prevent the growth of fungi andmicroorganisms. Suitable antifungal and antimicrobial agents include,but are not limited to, benzoic acid, butylparaben, ethyl paraben,methyl paraben, propylparaben, sodium benzoate, sodium propionate,benzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,and thimerosal.

In certain embodiments, it may be desirable to provide continuousdelivery of one or more compounds to a patient in need thereof. Fortopical applications, repeated application can be done or a patch can beused to provide continuous administration of the compounds over anextended period of time.

D. Pulmonary Formulations

In one embodiment, the compounds are formulated for pulmonary delivery,such as intranasal administration or oral inhalation. The respiratorytract is the structure involved in the exchange of gases between theatmosphere and the blood stream. The lungs are branching structuresultimately ending with the alveoli where the exchange of gases occurs.The alveolar surface area is the largest in the respiratory system andis where drug absorption occurs. The alveoli are covered by a thinepithelium without cilia or a mucus blanket and secrete surfactantphospholipids. The respiratory tract encompasses the upper airways,including the oropharynx and larynx, followed by the lower airways,which include the trachea followed by bifurcations into the bronchi andbronchioli. The upper and lower airways are called the conductingairways. The terminal bronchioli then divide into respiratorybronchiole, which then lead to the ultimate respiratory zone, thealveoli, or deep lung. The deep lung, or alveoli, is the primary targetof inhaled therapeutic aerosols for systemic drug delivery.

Pulmonary administration of therapeutic compositions comprised of lowmolecular weight drugs has been observed, for example, beta-androgenicantagonists to treat asthma. Other therapeutic agents that are active inthe lungs have been administered systemically and targeted via pulmonaryabsorption. Nasal delivery is considered to be a promising technique foradministration of therapeutics for the following reasons: the nose has alarge surface area available for drug absorption due to the coverage ofthe epithelial surface by numerous microvilli, the subepithelial layeris highly vascularized, the venous blood from the nose passes directlyinto the systemic circulation and therefore avoids the loss of drug byfirst-pass metabolism in the liver, it offers lower doses, more rapidattainment of therapeutic blood levels, quicker onset of pharmacologicalactivity, fewer side effects, high total blood flow per cm³, porousendothelial basement membrane, and it is easily accessible.

The term aerosol as used herein refers to any preparation of a fine mistof particles, which can be in solution or a suspension, whether or notit is produced using a propellant. Aerosols can be produced usingstandard techniques, such as ultrasonication or high-pressure treatment.

Carriers for pulmonary formulations can be divided into those for drypowder formulations and for administration as solutions. Aerosols forthe delivery of therapeutic agents to the respiratory tract are known inthe art. For administration via the upper respiratory tract, theformulation can be formulated into a solution, e.g., water or isotonicsaline, buffered or un-buffered, or as a suspension, for intranasaladministration as drops or as a spray. Preferably, such solutions orsuspensions are isotonic relative to nasal secretions and of about thesame pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0to pH 7.0. Buffers should be physiologically compatible and include,simply by way of example, phosphate buffers. For example, arepresentative nasal decongestant is described as being buffered to a pHof about 6.2. One skilled in the art can readily determine a suitablesaline content and pH for an innocuous aqueous solution for nasal and/orupper respiratory administration.

Preferably, the aqueous solution is water, physiologically acceptableaqueous solutions containing salts and/or buffers, such as phosphatebuffered saline (PBS), or any other aqueous solution acceptable foradministration to a animal or human. Such solutions are well known to aperson skilled in the art and include, but are not limited to, distilledwater, de-ionized water, pure or ultrapure water, saline,phosphate-buffered saline (PBS). Other suitable aqueous vehiclesinclude, but are not limited to, Ringer's solution and isotonic sodiumchloride. Aqueous suspensions may include suspending agents such ascellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gumtragacanth, and a wetting agent such as lecithin. Suitable preservativesfor aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

In another embodiment, solvents that are low toxicity organic (i.e.nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethylacetate, tetrahydofuran, ethyl ether, and propanol may be used for theformulations. The solvent is selected based on its ability to readilyaerosolize the formulation. The solvent should not detrimentally reactwith the compounds. An appropriate solvent should be used that dissolvesthe compounds or forms a suspension of the compounds. The solvent shouldbe sufficiently volatile to enable formation of an aerosol of thesolution or suspension. Additional solvents or aerosolizing agents, suchas freons, can be added as desired to increase the volatility of thesolution or suspension.

In one embodiment, compositions may contain minor amounts of polymers,surfactants, or other excipients well known to those of the art. In thiscontext, “minor amounts” means no excipients are present that mightaffect or mediate uptake of the compounds in the lungs and that theexcipients that are present are present in amount that do not adverselyaffect uptake of compounds in the lungs.

Dry lipid powders can be directly dispersed in ethanol because of theirhydrophobic character. For lipids stored in organic solvents such aschloroform, the desired quantity of solution is placed in a vial, andthe chloroform is evaporated under a stream of nitrogen to form a drythin film on the surface of a glass vial. The film swells easily whenreconstituted with ethanol. To fully disperse the lipid molecules in theorganic solvent, the suspension is sonicated. Nonaqueous suspensions oflipids can also be prepared in absolute ethanol using a reusable PARI LCJet+ nebulizer (PARI Respiratory Equipment, Monterey, Calif.).

Dry powder formulations (“DPFs”) with large particle size have improvedflowability characteristics, such as less aggregation, easieraerosolization, and potentially less phagocytosis. Dry powder aerosolsfor inhalation therapy are generally produced with mean diametersprimarily in the range of less than 5 microns, although a preferredrange is between one and ten microns in aerodynamic diameter. Large“carrier” particles (containing no drug) have been co-delivered withtherapeutic aerosols to aid in achieving efficient aerosolization amongother possible benefits.

Polymeric particles may be prepared using single and double emulsionsolvent evaporation, spray drying, solvent extraction, solventevaporation, phase separation, simple and complex coacervation,interfacial polymerization, and other methods well known to those ofordinary skill in the art. Particles may be made using methods formaking microspheres or microcapsules known in the art. The preferredmethods of manufacture are by spray drying and freeze drying, whichentails using a solution containing the surfactant, spraying to formdroplets of the desired size, and removing the solvent.

The particles may be fabricated with the appropriate material, surfaceroughness, diameter and tap density for localized delivery to selectedregions of the respiratory tract such as the deep lung or upper airways.For example, higher density or larger particles may be used for upperairway delivery. Similarly, a mixture of different sized particles,provided with the same or different EGS may be administered to targetdifferent regions of the lung in one administration.

Formulations for pulmonary delivery include unilamellar phospholipidvesicles, liposomes, or lipoprotein particles. Formulations and methodsof making such formulations containing nucleic acid are well known toone of ordinary skill in the art. Liposomes are formed from commerciallyavailable phospholipids supplied by a variety of vendors includingAvanti Polar Lipids, Inc. (Biuuingham, Ala.). In one embodiment, theliposome can include a ligand molecule specific for a receptor on thesurface of the target cell to direct the liposome to the target cell.

E. Other Active Agents

The compounds described herein can be co-administered with one or moreadditional active agents, such as diagnostic agents, therapeutic agents,and/or prophylactic agents. Suitable classes of active agents include,but are not limited to:

Alkylating agents, such as nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, ifosfamide, melphalan, and chlorambucil),ethylenimines and methylmelamines (e.g., heaxmethylmelamine), alkylsulfonates (e.g., thiotepa and busulfan) nitrosoureas (e.g., carmustine,lomustine, semustine, and streptozocin), and triazines (e.g.,dacarbazine);

Antimetabolites, such as folic acid and analogs thereof (e.g.,methotrexate), pyrimidine analogs (e.g., fluoracil, floxuridine, andcytarabine), purine analogs and related inhibitors (e.g.,mercaptopurine, thioguanine, and pentostatin),

Cytotoxic anticancer agents, such as paclitaxel;

Cytostatic and/or cytotoxic agents such as anti-angiogenic agents suchas endostatin, angiostatin, thalidomide;

Analgesics, such as opioid and non-opioid analgesics; and

Vaccines containing cancer antigens or immunomodulators such ascytokines to enhance the anti-cancer activity;

Natural products, such as vinca alkaloids (e.g., vinblastine andvincristine), epipodophyllotoxins (e.g., etoposide and tertiposide),antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin,plicamycin, and mitomycin), enzymes (e.g., L-asparaginase), andbiological response modifiers (e.g., interferon alpha);

Proteasome inhibitors, such as lactacystin, MG-132, and PS-341; Tyrosinekinase inhibitors, such as Gleevece, ZD 1839 (Iressa®), SH268,genistein, CEP2563, SU6668, SUI 1248, and EMD 121974;

Retinoids and synthetic retinoids, such as bexarotene, tretinoin,13-cis-retinoic acid, 9-cis-retinoic acid,.alpha.-difluoromethylomithine, ILX23-7553, fenretinide, andN-4-carboxyphenyl retinamide;

Cyclin-dependent kinase inhibitors, such as flavopiridol, UCN-01,roscovitine and olomoucine;

COX-2 inhibitors include, such as celecoxib, valecoxib, and rofecoxib;

Prenylprotein transferase inhibitors, such as RI 15777, SCH66336,L-778,123, BAL9611 and TAN-1813;

Hormones and antagonists, such as adrenocorticosteroids (e.g.,prednisone), progestins (e.g, hydroxyprogesterone caproate,medroxyprogesterone acetate, and megestrol acetate), estrogens (e.g.,diethylstilbestrol and ethinyl estradiol), antiestrogen (e.g.,tamoxifen), androgens (e.g., testosterone propionate, fluoxtnesterone,antiandrogen), and gonadotropin-releasing hormone analogs;

Sigma-2 receptor agonists, such as CB-64D, CB-184 and haloperidol;

HMG-CoA reductase inhibitors, such as lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and cerivastatin;

HIV protease inhibitors, such as amprenavir, abacavir, CGP-73547,CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir,saquinavir, ABT-378, AG 1776, and BMS-232,632;

Proteins include insulin, and

Miscellaneous compounds include platinum coordination complexes (e.g.,cisplatin and carboplatin), anthracenedione (e.g., mitoxantrone),substituted urea (hydroxyurea), methyl hydrazines (e.g., procarbazine),and adrenocortical suppressants (e.g., mitotane and aminogluethimide).

The one or more compounds and the one or more additional active agentscan be formulated in the same dosage form or separate dosage forms.Alternatively, the one or more additional active agents can beadministered simultaneously or almost simultaneously in different dosageforms. If in separate dosage units, the one or more compounds and theone or more additional active agents can be administered by the sameroute of administration or by different routes of administration. Forexample, the one or more compounds and the one or more additional activeagents can both be administered parenterally, or one can be administeredparenterally and one orally.

If the one or more compounds and the one or more active agents areadministered sequentially, the second agent to be administered isadministered typically less than 6 hours following administration of thefirst agent, preferably less than 4 hours after the first agent, morepreferably less than 2 hours after the first agent, more preferably lessthan 1 hour after the first agent, most preferably less than 30 minutesafter administration of the first agent, and most preferably immediatelyafter administration of the first agent. “Immediately”, as used here,means less than 10 minutes, preferably less than 5 minutes, morepreferably less than 2 minutes, most preferably less than one minute.

The compounds and the one or more additional active agents can beformulated for controlled release, for example, immediate release,delayed release, extended release, pulsatile release, and combinationsthereof. In one embodiment, the one or more compounds are formulated forimmediate release and the one or more additional agents are formulatedfor delayed, extended, or pulsatile release. In another embodiment, theone or more compounds are formulated for delayed, extended, or pulsatilerelease and the one or more additional active agents are formulated forimmediate release. In still another embodiment, the one or morecompounds and the one or more additional active agents are independentlyformulated for delayed, extended, or pulsatile release.

IV. Methods of Making the Compounds

The starting N-substituted 4-piperidones were synthesized usingliterature procedures. In general, treatment of 4-piperidonehydrochloride with p-toluene sulphonyl chloride, or benzene sulphonylchloride or benzyl bromide or ethyl iodide in presence of anhydrousK₂CO₃ at room temperature in biphasic medium [CHCl₃:H₂O (1:1)] yieldeddesired compounds (2a-d) in good yield (scheme 1). The acid catalyzedClaisen-Schmidt condensation of compounds 2a-d with variety ofsubstituted benzaldehydes under reflux temperature led to the formationof desired compounds (3a-j, 4a-j, 5a j, 6a-j) in good to excellent yield(scheme 1).

C5-curcuminoid-triazole hybrids were prepared as shown in scheme 3. Thestarting azides were prepared by literature method as shown in scheme 2.The alkyl bromide (7a-c) on refluxing with sodium azide in presence ofanhydrous K₂CO₃ and DMF affords desired compounds (8a-c) in good yield(scheme 2).

The alkyne counterparts for click reaction were prepared as shown inscheme 3. The compound 9 was synthesized via nucleophilic substitutionreaction between 4-piperidone hydrochloride monohydrate and propargylbromide in presence of anhydrous K₂CO₃ in the biphasic system [CHCl₃:H₂O(1:1)] at room temperature in good yield. The compound 9 was reactedwith substituted benzaldehydes in presence of 20% NaOH solution inethanol to give compounds (11a-c, 12a-c, 13a-c, 14a-c, 15a-c, 16a-c) invery good yield (scheme 3).

V. Methods of Using the Compounds

The compounds described herein can be administered to a subject in needthereof to treat the subject either prophylactically (i.e., to preventcancer) or therapeutically (i.e., to treat cancer after it has beendetected), including reducing tumor growth, reducing the risk of localinvasiveness of a tumor, increasing survival time of the patient, and/orreducing the risk of metastasis of a primary tumor.

The compounds described herein can contact a target cell to inhibit theinitiation and promotion of cancer, to kill cancer/malignant cells, toinhibit cell growth, to induce apoptosis, to inhibit metastasis, todecrease tumor size, to otherwise reverse or reduce the malignantphenotype of tumor cells, and combinations thereof. This may be achievedby contacting a tumor or tumor cell with a single composition orpharmacological formulation that includes the compound(s), or bycontacting a tumor or tumor cell with more than one distinct compositionor formulation, simultaneously, wherein one composition includes one ormore compounds described herein and the other includes a second agent.

Exemplary cancers, which can be treated, include, but are not limitedto, cancer of the skin, colon, uterine, ovarian, pancreatic, lung,bladder, breast, renal system, and prostate. Other cancers include, butare not limited to, cancers of the brain, liver, stomach, esophagus,head and neck, testicles, cervix, lymphatic system, larynx, esophagus,parotid, biliary tract, rectum, endometrium, kidney, and thyroid;including squamous cell carcinomas, adenocarcinomas, small cellcarcinomas, gliomas, neuroblastomas, and the like. Assay methods forascertaining the relative efficacy of the compounds described herein intreating the above types of cancers as well as other cancers are wellknown in the art.

The compounds described herein can also be used to treat metastaticcancer either in patients who have received prior chemo, radio, orbiological therapy or in previously untreated patients. In oneembodiment, the patient has received previous chemotherapy. Patients canbe treated using a variety of routes of administration includingsystemic administration, such as intravenous administration orsubcutaneous administration, oral administration or by intratumoralinjection.

The compounds described herein can also be used to treat patients whohave been rendered free of clinical disease by surgery, chemotherapy,and/or radiotherapy. In these aspects, the purpose of therapy is toprevent or reduce the likelihood of recurrent disease. Adjuvant therapycan be administered in the same regimen as described above to preventrecurrent disease.

The compositions described herein contain an effective amount of the oneor more of the compounds described herein. The amount to be administeredcan be readily determined by the attending physician based on a varietyof factors including, but not limited to, age of the patient, weight ofthe patient, disease or disorder to be treated, presence of apre-existing condition, and dosage form to be administered (e.g.,immediate release versus modified release dosage form). Typically, theeffective amount is from about 0.1 mg/kg/day to about 200 mg/kg/day,more preferably from 0.1 mg/kg/day to 50 mg/kg/day, more preferably from0.1 mg/kg/day to 25 mg/kg/day, and most preferably from 0.1 mg/kg/day to10 mg/kg/day. Dosages greater or less than this may be administereddepending on the diseases or disorder to be treated.

EXAMPLES Example 1 Synthesis and Characterization of1-tosyl-piperidin-4-one (2a) and Related Compounds (2a-d)

Compounds 2a-d were prepared by literature methods and characterizedspectroscopically. In a typical reaction, 4-piperidone hydrochloridemonohydrate 1 (5 g, 29.13 mmol) was dissolved in 20 mL of a biphasicsystem of CHCl₃:H₂O (1:1). To this reaction mixture, K₂CO₃ (12.06 g,87.40 mmol) was added followed by the addition of p-toluenesulphonylchloride (5.5 g, 29.13 mmol). The reaction was stirred at roomtemperature for 4 h and progress of the reaction was monitored by thinlayer chromatography. After completion, reaction mixture was extractedwith chloroform. The organic layer was dried over Na₂SO₄ and excess ofsolvent was removed under vacuum. The crude product was purified bysilica gel column using EtOAc/Hexane as an eluent to afford the desiredcompound as white solid. Yield: 8.24 g (88%); mp: 142° C.; IR (Film,cm⁻¹): 2966, 2927, 2879, 1713 (C═O), 1369, 1348, 1225, 1171, 965, 691;¹H NMR (400 MHz, CDCl₃): δ=2.44 (s, 3H, PhCH₃), 2.53 (t, J=5.8 Hz, 4H,2×CH₂CH₂NTs), 3.38 (t, J=5.8 Hz, 4H, 2×CH₂CH₂NTs), 7.33 (d, J=8.0 Hz,2H, ArH), 7.67 (d, J=8.0 Hz, 2H, ArH); ESI-MS (m/z): 254.08 (M⁺+H).

Example 2 Synthesis of1-benzyl-3,5-bis(4-propylbenzylidene)piperidin-4-one (5d) and relatedcompounds (3a-j, 4a-j, 5a-j, 6a-j)

Compound 2c (250 mg, 1.32 mmol) and 4-propylbenzaldehyde (391 mg, 2.64mmol) were dissolved in 20 mL of EtOH at 0° C. To this reaction mixture2 mL of 35-38% HCl was added. After 15-20 minutes of stirring at roomtemperature, the reaction mixture was refluxed for 6 h. The precipitatedyellow compound was filtered and washed with EtOH. Crude product wascrystallized in EtOH to get compound 5d in pure form. Yield: 368 mg(83%); mp: 113° C.; IR (Film): v{tilde over ( )}=3026, 2959, 2930, 2871,1672 (C═O), 1608, 1509, 1454, 1301, 1263, 1195, 1178, 1001, 699; ¹H NMR(400 MHz, CDCl₃): δ=0.94 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₃), 1.61-1.65(in, 4H, 2×PhCH₂CH₂CH₃), 2.59 (t, J=8.0 Hz, 4H, 2×PhCH₂CH₂CH₃), 3.70 (s,2H, NCH₂Ph), 3.86 (s, 4H, CH₂NCH₂), 7.17 (d, J=8.0 Hz, 4H, ArH),7.22-7.27 (m, 9H, ArH), 7.78 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.90 (CH₃), 22.29 (CH₂), 35.46 (CH₂), 54.36 (CH₂), 61.24(CH₂), 127.24 (CH), 128.25 (CH), 128.59 (CH), 128.98 (CH), 130.46 (CH),132.46 (Cquart), 132,60 (Cquart), 136.61 (CH), 144.21 (Cquart), 187.78(CO) ppm; ESI-MS (m/z): 450.27 (M⁺+H); Anal. calcd for C₃₂H₃₅NO: C,85.48; H, 7.85; N, 3.12; Found: C, 85.46; H, 7.88; N, 3.10.

3,5-Bis(4-bromobenzylidene)-1-tosylpiperidin-4-one (3a): Yield: 75%; mp:214° C.; IR (Film): v{tilde over ( )}=2919, 2850, 1675 (C═O), 1485,1343, 1160, 1071, 742; ¹H NMR (400 MHz, CDCl₃): δ=2.43 (s, 3H, PhCH₃),4.53 (s, 4H, CH₂NCH₂), 7.19-7.24 (m, 6H, ArH), 7.48 (d, J=8.2 Hz, 4H,ArH), 7.59-7.63 (m, 4H, ArH, 2×C═CHPh) ppm; ESI-MS (m/z): 585.92 (M⁺+H);Anal. calcd for C₂₆H₂₁Br₂NO₃S: C, 53.17; H, 3.60; N, 2.38; Found: C,53.15; H, 3.58; N, 2.37.

3,5-Bis(4-etbylbenzylidene)-1-tosylpiperidin-4-one (3b): Yield: 72%; mp:165° C.; IR (Film): v{tilde over ( )}=2964, 2922, 2851, 1675 (C═O),1605, 1510, 1347, 1266, 1169, 1090, 835, 762, 667; ¹H NMR (400 MHz,CDCl₃): δ=1.27 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₃), 2.42 (s, 3H, PhCH₃), 2.68(q, J=7.3 Hz, 4H, 2×PhCH₂CH₃), 4.63 (s, 4H, CH₂NCH₂), 7.20 (d, J=8.2 Hz,2H, ArH), 7.26-7.28 (m, 6H, ArH), 7.48 (d, J=8.2 Hz, 4H, ArH), 7.68 (s,2H, 2×C═CHPh) ppm; ESI-MS (m/z): 486.20 (M⁺+H); Anal. calcd forC₃₀H₃₁NO₃S: C, 74.20; H, 6.43; N, 2.88; Found: C, 74.22; 11, 6.41; N,2.86.

3,5-Bis(4-propylbenzylidene)-1-tosylpiperidin-4-one (3c): Yield: 78%;mp: 157° C.; IR (Film): v{tilde over ( )}=2958, 2924, 1675 (C═O), 1605,1348, 1263, 1237, 1169, 1089, 994, 966, 866, 665; ¹H NMR (400 MHz,CDCl₃): δ=0.96 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₃), 1.68-1.70 (m, 4H,2×PhCH₂CH₂CH₃), 2.42 (s, 3H, PhCH₃), 2.62 (t, J=7.8 Hz, 4H,2×PhCH₂CH₂CH₃), 4.63 (s, 4H, CH₂NCH₂), 7.20 (d, J=8.2 Hz, 4H, ArH),7.26-7.27 (m, 4H, ArH), 7.48 (d, J=8.2 Hz, 4H, ArH), 7.67 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.85, 21.58, 24.28, 37.91,47.30, 127.60, 129.01, 129.14, 129.64, 130.48, 131.86, 138.53, 184.94ppm; ESI-MS (m/z): 514.23 (M⁺+H); Anal. calcd for C₃₂H₃₅NO₃S: C, 74.82;H, 6.87; N, 2.73; Found: C, 74.81; H, 6.85; N, 2.75.

3,5-Bis(4-methylbenzylidene)-1-tosylpiperidin-4-one (3d): Yield: 81%;mp: 187° C.; IR (Film): v{tilde over ( )}=2919, 2851, 1678 (C═O), 1606,1511, 1348, 1265, 1178, 1168, 992, 815, 667; ¹HNMR (400 MHz, CDCl₃):δ=2.42 (s, 9H, 3×CH₃), 4.62 (s, 4H, CH₂NCH₂), 7.20 (d, J=8.2 Hz, 4H,ArH), 7.23-7.26 (m, 4H, ArH), 7.46 (d, J=8.2 Hz, 4H, ArH), 7.66 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=21.57, 47.27, 127.56, 129.19,129.62, 130.45, 131.62, 138.52, 140.14, 143.95, 184.99 ppm; ESI-MS(m/z): 458.17 (M⁺+H); Anal. calcd. for C₂₈H₂₇NO₃S: C, 73.49; H, 5.95; N,3.06; Found: C, 73.52; H, 5.97; N, 3.02.

3,5-Bis(4-chlorobenzylidene)-1-tosylpiperidin-4-one (3e): Yield: 80%;mp: 209° C.; IR (Film): v{tilde over ( )}=2919, 2850, 1607, 1483, 1343,1160, 1087, 947, 829, 792, 742, 677; ¹H NMR (400 MHz, CDCl₃): δ=2.43 (s,3H, PhCH₃), 4.55 (s, 4H, CH₂NCH₂), 7.23 (d, J=7.8 Hz, 4H, ArH),7.26-7.28 (m, 2H, ArH), 7.42 (d, J=7.8 Hz, 4H, ArH), 7.48 (d, J=7.8 Hz,2H, ArH), 7.65 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 498.06 (M⁺+H);500.12 (M⁺+2), 502.12 (M⁺+4); Anal. calcd. for C₂₆H₂₁Cl₂NO₃S: C, 62.65;H, 4.25; N, 2.81; Found: C, 62.63; H, 4.26; N, 2.80.

3,5-Bis(4-methoxybenzylidene)-1-tosylpiperidin-4-one (3f): Yield: 68%;mp: 183° C.; IR (Film): v{tilde over ( )}=2933, 2838, 1671 (C═O), 1598,1510, 1459, 1349, 1257, 1171, 1030, 965, 830, 669; ¹H NMR (400 MHz,CDCl₃): δ=2.41 (s, 3H, PhCH₃), 3.88 (s, 6H, 2×PhOCH₃), 4.62 (s, 4H,CH₂NCH₂), 6.97 (d, J=8.2 Hz, 4H, ArH), 7.20 (d, J=8.2 Hz, 2H, ArH), 7.31(d, J=8.2 Hz, 4H, ArH), 7.48 (d, J=8.2 Hz, 2H, ArH), 7.64 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=21.58, 47.24, 55.41, 114,127.56, 128.01, 129.63, 132.37, 134.77, 138.07, 143.92, 160.75, 184.89ppm; ESI-MS (m/z): 490.16 (M⁺+H); Anal. caled for C₂₈H₂₇NO₅S: C, 68.69;H, 5.56; N, 2.86; Found: C, 68.68; H, 5.58; N, 2.88.

3,5-Bis(4-tert-butylbenzylidene)-1-tosylpiperidin-4-one (3g): Yield:78%; mp: 220° C.; IR (Film): v{tilde over ( )}=2962, 2870, 1672 (C═O),1612, 1581, 1413, 1346, 1262, 1184, 1162, 1037, 962, 846, 758, 682, 673;¹H NMR (400 MHz, CDCl₃): δ=1.31 (s, 18H, 2×PhC(CH₃)₃), 2.37 (s, 3H,PhCH₃), 4.58 (s, 4H, CH₂NCH₂), 7.17-7.21 (m, 2H, ArH), 7.24-7.26 (m, 4H,ArH), 7.41-7.46 (m, 6H, ArH), 7.64 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100MHz, CDCl₃): δ=21.59, 31.12, 34.89, 47.36, 125.87, 127.62, 129.64,130.35, 131.58, 134.60, 143.98, 153.16, 184.68 ppm; ESI-MS (m/z): 542.27(M⁺+H); Anal. caled for C₃₄H₃₉NO₃S: C, 75.38; H, 7.26; N, 2.59; Found:C, 75.39; H, 7.28; N, 2.57.

3,5-Bis(4-butylbeinylidene)-1-tosylpiperidin-4-one (3 h): Yield: 85%;mp: 148° C.; IR (Film): v{tilde over ( )}=2957, 2928, 2871, 2859, 1676(C═O), 1604, 1510, 1350, 1265, 1241, 1181, 1169, 997, 869, 821, 666; ¹HNMR (400 MHz, CDCl₃): δ=0.94 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₂CH₃),1.36-1.40 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.59-1.64 (m, 4H,2×PhCH₂CH₂CH₂CH₃), 2.42 (s, 3H, PhCH₃), 2.65 (t, J=8.2 Hz, 4H,2×PhCH₂CH₂CH₂CH₃), 4.63 (s, 4H, CH₂NCH₂), 7.21 (d, J=8.2 Hz, 2H, ArH),7.26-7.27 (m, 6H, ArH), 7.48 (d, J=8.2 Hz, 4H, ArH), 7.67 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.92, 21.57, 22.35, 33.30,35.55, 47.30, 127.59, 128.96, 129.12, 129.64, 130.49, 131.81, 138.54,145.12, 184.94 ppm; ESI-MS (m/z): 542.27 (M⁺+H); Anal. calcd forC₃₄H₃₉NO₃S: C, 75.38; H, 7.26; N, 2.59; Found: C, 75.36; H, 7.23; N,2.57.

3,5-Bis(4-isopropylbenzylidene)-1-tosylpiperidin-4-one (3i): Yield: 71%;mp: 177° C.; IR (Film): v{tilde over ( )}=2951, 2927, 2861, 2859, 1675(C═O), 1614, 1510, 1450, 1265, 1241, 1182, 1169, 997; ¹H NMR (400 MHz,CDCl₃): δ=1.29 (d, J=6.8 Hz, 12H, 2×PhCH(CH₃)₂), 2.42 (s, 3H, PhCH₃),2.91-3.01 (m, 2H, 2×PhCH(CH₃)₂), 4.63 (s, 4H, CH₂NCH₂), 7.22 (d, J=8.2Hz, 4H, ArH), 7.28-7.33 (m, 6H, ArH), 7.49 (d, J=8.2 Hz, 2H, ArH), 7.68(s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=21.58, 23.73, 34.06,47.34, 27.00, 127.60, 129.14, 129.64, 130.60, 131.97, 138.53, 150.92,184.91 ppm; ESI-MS (m/z): 514.23 (M⁺+H); Anal. calcd for C₃₂H₃₅NO₃S: C,74.82; H, 6.87; N, 2.73; Found: C, 74.84; H, 6.86; N, 2.75.

3,5-Bis(4-fluorobenzylidene)-1-tosylpiperidin-4-one (3j): Yield: 73%;mp: 204° C.; IR (Film): v{tilde over ( )}=3023, 1669 (C═O), 1599, 1573,1505, 1342, 1223, 1154, 1086, 1041, 946, 835, 745, 677; ¹H NMR (400 MHz,CDCl₃): δ=2.43 (s, 3H, PhCH₃), 4.51 (s, 4H, CH₂NCH₂), 7.13-7.18 (m, 4H,ArH), 7.23 (d, J=7.8 Hz, 2H, ArH), 7.32-7.36 (m, 2H, ArH), 7.49-7.51 (m,4H, ArH), 7.67 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 466.12 (M⁺+H); Anal.calcd for C₂₆H₂₁F₂NO₃S: C, 67.08; H, 4.55; N, 3.01; Found: C, 67.37; H,4.70; N, 3.02.

3,5-Bis(4-methylbenzyliderre)-1-(phenylsulfonyl)piperidin-4-one (4a):Yield: 67%; mp: 211° C.; IR (Film): v{tilde over ( )}=2920, 2850, 1605,1463, 1349, 1263, 1171, 1091, 994, 814; ¹H NMR (400 MHz, CDCl₃): δ=2.42(s, 6H, 2×PhCH₃), 4.67 (s, 4H, CH₂NCH₂), 7.24-7.29 (m, 8H, ArH),7.40-7.43 (m, 2H, ArH), 7.55-7.58 (m, 3H, ArH), 7.65 (s, 2H, 2×C═CHPh)ppm; ¹³C NMR (100 MHz, CDCl₃): δ=21.48, 47.27, 127.48, 129.00, 129.03,129.64, 130.46, 138.62, 184.82 ppm; ESI-MS (m/z): 444.16 (M⁺+H); Anal.calcd for C₂₇H₂₅NO₃S: C, 73.11; H, 5.68; N, 3.16; Found: C, 73.05; H,5.86; N, 3.10.

3,5-Bis(4-ethylbenzylidene)-1-(phenyisulfonyl)piperidin-4-one (4b):Yield: 77%; mp: 165° C.; IR (Film): v{tilde over ( )}=2965, 2922, 2851,1678 (C═O), 1604, 1584, 1350, 1262, 1172, 1155, 972, 867, 838, 829, 760;¹H NMR (400 MHz, CDCl₃): δ=1.27 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₃), 2.69(q,J=7.7 Hz, 4H, 2×PhCH₂CH₃), 4.68 (s, 4H, CH₂NCH₂), 7.26-7.31 (m, 8H,ArH), 7.40-7.44 (m, 2H, ArH), 7.55-7.59 (m, 3H, ArH), 7.65 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=15.23, 28.78, 47.31, 127.51,128.44, 129.01, 130.57, 131.79, 133.11, 138.66, 146.42, 184.79 ppm;ESI-MS (m/z): 472.19 (M⁺+H); Anal. calcd for C₂₉H₂₉NO₃S: C, 73.86; H,6.20; N, 2.97; Found: C, 73.93; H, 6.38; N, 2.92.

3,5-Bis(4-isopropylbenzylidene)-1-(phenyisulfonyl)piperidin-4-one (4c):Yield: 72%; mp: 170° C.; IR (Film): v{tilde over ( )}=2959, 2921, 2851,1668 (CO), 1606, 1463, 1347, 1265, 1241, 1166, 1090, 956, 835, 740; ¹HNMR (400 MHz, CDCl₃): δ=1.29 (d, J=6.8 Hz, 12H, 2×PhCH(CH₃)₂), 2.95-2.97(m, 2H, 2×PhCH(CH₃)₂), 4.68 (s, 4H, CH₂NCH₂), 7.27-7.34 (m, 8H, ArH),7.41-7.44 (m, 2H, ArH), 7.55-7.61 (m, 3H, ArH), 7.66 (s, 2H, 2×C═CHPh)ppm; ¹³C NMR (100 MHz, CDCl₃): δ=23.73, 34.07, 47.35, 127.03, 127.54,129.01, 130.61, 131.92, 133.12, 137.88, 150.97, 184.74 ppm; ESI-MS(m/z): 500.22 (M⁺+H); Anal. calcd for C₃₁H₃₃NO₃S: C, 74.52; 11, 6.66; N,2.80; Found: C, 74.55; H, 6.63; N, 2.82.

1-(Phenyisulfonyl)-3,5-bis(4-propylbenzylidene)piperidin-4-one (4d):Yield: 69%; mp: 153° C.; IR (Film): v{tilde over ( )}=2952, 1704 (C═O),1505, 1443, 1232, 1035, 10313, 808, 757; ¹H NMR (400 MHz, CDCl₃): δ=0.94(t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₃), 1.64-1.68 (m, 4H, 2×PhCH₂CH₂CH₃), 2.60(t, J=7.6 Hz, 4H, 2×PhCH₂CH₂CH₃), 4.65 (s, 4H, CH₂NCH₂), 7.24-7.25 (n,3H, ArH), 7.37-7.41 (m, 3H, ArH), 7.52-7.58 (m, 7H, ArH), 7.63 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.85, 24.28, 37.91, 47.30,127.51, 128.98, 129.03, 130.50, 131.12, 138.67, 144.97, 184.82 ppm;ESI-MS (m/z): 501.22 (M⁺+H); Anal. callc for C₃₁H₃₃NO₃S: C, 74.52; H,6.66; N, 2.80; Found: C, 73.30; H, 6.21; N, 2.79.

3,5-Bis(4-chlorobenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4e):Yield: 74%; mp: 237° C.; IR (Film): v{tilde over ( )}=2920, 2851, 1610,1490, 1166, 1092, 809; ¹H NMR (400 MHz, CDCl₃): δ=4.60 (s, 4H, CH₂NCH₂),7.26-7.29 (m, 5H, ArH), 7.43-7.46 (m, 6H, ArH), 7.58-7.61 (m, 2H, ArH),7.64 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 484.05 (M⁺+H), 486.12 (M⁺+2),488.08 (M⁺+4); Anal. calcd for C₂₅H₁₉Cl₂NO₃S: C, 61.99; H, 3.95; N,2.89; Found: C, 60.77; H, 4.02; N, 2.71.

3,5-Bis(4-tert-butylbenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4f):Yield: 68%; mp: 194° C.; IR (Film): v{tilde over ( )}=2963, 2869, 1672(C═O), 1608, 1583, 1352, 1264, 1185, 1166, 990, 756, 724; ¹H NMR (400MHz, CDCl₃): δ=1.37 (s, 18H, 2×PhC(CH₃)₃), 4.69 (s, 4H, CH₂NCH₂), 7.29(d, J=8.2 Hz, 4H, ArH), 7.41-7.49 (m, 6H, ArH), 7.56-7.62 (m, 3H, ArH),7.67 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=31.13, 34.92,47.37, 125.91, 127.56, 129.03, 130.38, 131.53, 133.13, 138.56, 153.24,148.23 ppm; ESI-MS (m/z): 529.25 (M⁺+H); Anal. calcd for C₃₃H₃₇NO₃S: C,75.11; H, 7.07; N, 2.65; Found: C, 75.13; H, 7.02; N, 2.61.

3,5-Bis(4-butylbenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4g):Yield: 76%; mp: 134° C.; IR (Film): v{tilde over ( )}=2956, 2930, 2858,1676 (C═O), 1605, 1446, 1352, 1265, 1168, 1090, 691; ^(I)H NMR (400 MHz,CDCl₃): δ=0.94 (t, J=7.0 Hz, 6H, 2×PhCH₂CH₂CH₂CH₃), 1.35-1.42 (m, 4H,2×PhCH₂CH₂CH₂CH₃), 1.59-1.64 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 2.65 (t, J=7.8Hz, 4H, 2×PhCH₂CH₂CH₂CH₃), 4.68 (s, 4H, CH₂NCH₂), 7.26-7.27 (m, 4H,ArH), 7.42-7.44 (m, 4H, ArH), 7.55-7.60 (m, 5H, ArH), 7.66 (s, 2H,2×C═CHPh) ppm; ESI-MS (m/z): 528.25 (M⁺+H); Anal. calcd for C₃₃H₃₇NO₃S:C, 75.11; H, 7.07; N, 2.65; Found: C, 75.12; H, 7.11; N, 2.66.

3,5-Bis(4-methoxybenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4 h):Yield: 71%; mp: 217° C.; IR (Film): v{tilde over ( )}=2918, 2850, 1670(C═O), 1595, 1506, 1460, 1349, 1252, 1234, 1169, 1028, 991, 837; ¹H NMR(400 MHz, CDCl₃): δ=3.88 (s, 6H, 2×PhOCH₃), 4.67 (s, 4H, CH₂NCH₂), 6.97(d, J=8.6 Hz, 4H, ArH), 7.31 (d, J=8.6 Hz, 4H, ArCH), 7.41-7.43 (m, 2H,ArH), 7.54-7.63 (m, 5H, ArH, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃):δ=47.25, 55.42, 114.42, 127.08, 127.48, 127.83, 128.99, 132.40, 138.18,160.78, 184.74 ppm; ESI-MS (m/z): 476.15 (M⁺+H); Anal. calcd forC₂₇H₂₅NO₅S: C, 68.19; H, 5.30; N, 2.95; Found: C, 68.17; H, 5.36; N,2.99.

3,5-Bis(4-bromobenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4i):Yield: 77%; mp: 247° C.; IR (Film): v{tilde over ( )}=2920, 2850, 1674(C═O), 1219, 1071, 822, 772; ¹H NMR (400 MHz, CDCl₃): δ=4.59 (s, 4H,CH₂NCH₂), 7.19 (d, J=8.2 Hz, 2H, ArH), 7.42-7.46 (m, 4H, ArH), 7.58-7.62(m, 9H, ArH, 2×C═CHPh) ppm; ESI-MS (m/z): 571.95 (M⁺+H); Anal. calcd forC₂₅H₁₉Br₂NO₃S: C, 52.38; H, 3.34; N, 2.44; Found: C, 52.57; H, 3.14; N,2.46.

3,5-Bis(4-fluorobenzylidene)-1-(phenylsulfonyl)piperidin-4-one (4j):Yield: 73%; mp: 181° C.; IR (Film): v{tilde over ( )}=2922, 2851, 1670(C═O), 1600, 1507, 1345, 1227, 1158, 1088, 948, 835, 751; ¹H NMR (400MHz, CDCl₃): δ=4.62 (s, 4H, CH₂NCH₂), 7.15-7.19 (m, 4H, ArH), 7.32-7.36(m, 4H, ArH), 7.44-7.46 (m, 2H, ArH), 7.59-7.61 (m, 3H, ArH), 7.65 (s,2H, 2×C═CHPh) ppm; ESI-MS (m/z): 452.11 (M⁺+H); Anal. calcd forC₂₅H₁₉F₂NO₃S: C, 66.51; H, 4.24; N, 3.10; Found: C, 66.68; H, 4.42; N,3.03.

1-Benzyl-3,5-bis(4-methylbenzylidene)piperidin-4-one (5a): Yield: 78%;mp: 170° C.; IR (Film v{tilde over ( )}=2920, 2801, 1609, 1510, 1451,1264, 1178, 1000, 816; ¹H NMR (400 MHz, CDCl₃): δ=2.36 (s, 6H, 2×PhCH₃),3.71 (s, 2H, NCH₂Ph), 3.87 (s, 4H, CH₂NCH₂), 7.16-7.24 (m, 13H, ArH),7.78 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=21.39, 54.46,61.43, 128.30, 128.96, 129.25, 130.45, 132.43, 136.47, 187.79 ppm;ESI-MS (m/z): 394.21 (M⁺+H); Anal. calcd for C₂₈H₂₇NO: C, 85.46; H,6.92; N, 3.56; Found: C, 85.39; H, 6.95; N, 3.58.

1-Benzyl-3,5-bis(4-bromobenzylidene)piperidin-4-one (5b): Yield: 69%;mp: 151° C.; IR (Film): v{tilde over ( )}=3028, 2924, 2807, 2739, 1669(C═O), 1610, 1579, 1487, 1402, 1315, 1266, 1189, 1071, 1003, 819, 755;¹H NMR (400 MHz, CDCl₃): δ=3.69 (s, 2H, NCH₂Ph), 3.80 (s, 4H, CH₂NCH₂),7.15-7.25 (m, 9H, ArH), 7.47 (d, J=8.0 Hz, 4H, ArH), 7.71 (s, 2H,2×C═CHPh) ppm; ESI-MS (m/z): 522 (M⁺+H); Anal. calcd for C₂₆H₂₁Br₂NO: C,59.68; H, 4.05; N, 2.68; Found: C, 59.65; H, 4.07; N, 2.66.

1-Benzyl-3,5-bis-(4-ethyl-benzylidene)-piperidin-4-one (5c): Yield: 68%;mp: 119° C.; IR (Film): v{tilde over ( )}=3028, 2964, 2873, 2746, 1668(C═O), 1606, 1581, 1450, 1320, 1266, 1178, 1166, 1073, 932, 830, 752; ¹HNMR (400 MHz, CDCl₃): δ=1.22 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₃), 2.62CH₂NCH₂), 7.19-7.26 (m, 13H, ArH), 7.78 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR(100 MHz, CDCl₃): δ=15.25, 28.65, 54.39, 61.32, 128.00, 128.22, 128.90,130.50, 132.52, 132.61, 136.43, 145.42, 187.74 ppm; ESI-MS (m/z): 423.24(M⁺+2H); Anal. calcd for C₃₀H₃₁NO: C, 85.47; H, 7.41; N, 3.32; Found: C,85.44; H, 7.43; N, 3.35.

1-Benzyl-3,5-bis(4-isopropylbenzylidene)piperidin-4-one (5e): Yield:76%; mp: 157° C.; IR (Film): v{tilde over ( )}=2960, 2870, 1672 (C═O),1612, 1508, 1455, 1419, 1311, 1264, 1180, 1001, 830; ¹H NMR (400 MHz,CDCl₃): δ=1.21 (d, J=7.3 Hz, 12H, 2×PhCH(CH₃)₂), 2.89 (sept, 2H,2×PhCH(CH₃)₂), 3.73 (s, 2H, NCH₂Ph), 3.91 (s, 4H, CH₂NCH₂), 7.18-7.28(m, 13H, ArH), 7.81 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃):δ=23.76, 33.98, 54.42, 61.31, 126.63, 127.24, 128.27, 130.58, 132.84,136.48, 150.06, 187.87 ppm; ESI-MS (m/z): 450.27 (M⁺+H); Anal. calcd forC₃₂H₃₅NO: C, 85.48; H, 7.85; N, 3.12; Found: C, 85.42; H, 7.84; N, 3.08.

1-Benzyl-3,5-bis(4-butylbenzylidene)piperidin-4-one (5f): Yield: 75%;mp: 104° C.; IR (Film): v{tilde over ( )}=2956, 2929, 2858, 1673 (C═O),1613, 1509, 1455, 1418, 1305, 1264, 1195, 1177, 1001, 931, 829, 753; ¹HNMR (400 MHz, CDCl₃): δ=0.90 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₂CH₃),1.30-1.39 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.55-1.63 (m, 4H,2×PhCH₂CH₂CH₂CH₃), 2.59 (t, J=7.3 Hz, 4H, 2×PhCH₂CH₂CH₂CH₃), 3.71 (s,2H, NCH₂Ph), 3.88 (s, 4H, CH₂NCH₂), 7.16 (d, J=8.0 Hz, 4H, ArH).7.22-7.26 (m, 9H, ArH), 7.79 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.90, 22.29, 33.34, 35.46, 54.36, 61.24, 128.25, 128.59,128.98, 130.46, 132.60, 136.61, 144.21, 187.78 ppm; ESI-MS (m/z): 478.30(M⁺+H); Anal. calcd for C₃₄H₃₉NO: C, 85.49; H, 8.23; N, 2.93; Found: C,85.55; H, 8.21; N, 2.94.

1-Benzyl-3,5-bis(4-tert-butylbenzylidene)piperidin-4-one (5g): Yield:77%; mp: 167° C.; IR (Film): v{tilde over ( )}=2963, 2869, 1672 (C═O),1611, 1582, 1264, 1203, 1185, 1017, 1003, 830, 737; ¹H NMR (400 MHz,CDCl₃): δ=1.32 (s, 18H, 2×PhC(CH₃)₃), 3.71 (s, 2H, NCH₂Ph), 3.87 (s, 4H,CH₂NCH₂), 7.19-7.25 (m, 5H, ArH), 7.28 (d, J=8.2 Hz, 4H, ArH), 7.38 (d,J=8.2 Hz, 4H, ArH), 7.77 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=31.13, 34.78, 54.41, 61.30, 125.49, 128.27, 128.99, 130.33,132.70, 136.38, 152.30, 187.92 ppm; ESI-MS (m/z): 478.30 (M⁺+H); Anal.calcd for C₃₄H₃₉NO: C, 85.49; H, 8.23; N, 2.93; Found: C, 85.51; H,8.23; N, 2.97.

1-Benzyl-3,5-bis(4-methoxybenzylidene)piperidin-4-one (5 h): Yield: 70%;mp: 160° C. (lit. mp 150-154° C.); IR (Film): v{tilde over ( )}=2968,2838, 2745, 1670 (C═O), 1600, 1577, 1510, 1303, 1256, 1172, 1030, 830;¹H NMR (400 MHz, CDCl₃): δ=3.72 (s, 2H, NCH₂Ph), 3.82 (s, 4H, CH₂NCH₂),3.87 (s, 6H, 2×PhOCH₃), 6.88 (d, J=8.0 Hz, 4H, ArH), 7.18-7.31 (m, 9H,ArH), 7.77 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 426.20 (M⁺+H); Anal.calcd for C₂₈H₂₇NO₃: C, 79.03; H, 6.40; N, 3.29; Found: C, 79.08; H,6.42; N, 3.24.

1-Benzyl-3,5-bis(4-chlorobenzylidene)piperidin-4-one (5i): Yield: 73%;mp: 164° C.; IR (Film): v{tilde over ( )}=2926, 2810, 2738, 1670 (C═O),1612, 1580, 1490, 1267, 1190, 1094, 1004, 820.32, 756.02 ; ¹H NMR (400MHz, CDCl₃): δ=3.70 (s, 2H, NCH₂Ph), 3.80 (s, 4H, CH₂NCH₂), 7.24-7.25(m, 9H, ArH), 7.33 (d, J=8.2 Hz, 4H, ArH), 7.72 (s, 2H, 2×C═CHPh) ppm;¹³C NMR (100 MHz, CDCl₃): δ=54.19, 61.54, 128.39, 128.80, 128.90,131.49, 135.31, 187.36 ppm; ESI-MS (m/z): 434.10 (M⁺+H), 436.18 (M⁺+2),438.10 (M⁺+4); Anal. calcd C₂₆H₂₁Cl₂NO: C, 71.89; H, 4.87; N, 3.22; for;Found: C, 71.90; H, 4.88; N, 3.20.

1-Benzyl-3,5-bis(4-fluorobenzylidene)piperidin-4-one (5j): Yield: 77%;mp: 159° C.; IR (Film): v{tilde over ( )}=2810, 1670 (C═O), 1618, 1581,1508, 1455, 1238, 1191, 1005, 832, 791; ¹H NMR (400 MHz, CDCl₃): δ=3.67(s, 2H, NCH₂Ph), 3.80 (s, 4H, CH₂NCH₂), 7.16-7.24 (m, 9H, ArH), 7.27 (d,J=8.8 Hz, 4H, ArH), 7.71 (s, 2H, 2×C′CHPh) ppm; ESI-MS (m/z): 402.16(M⁺+H); Anal. calcd for C₂₆H₂₁F₂NO: C, 77.79; H, 5.27; N, 3.49; Found:C, 76.85; H, 5.33; N, 3.47.3,5-Bis-(4-bromo-benzylidene)-1-ethyl-piperidin-4-one (6a): Yield: 64%;mp: 178° C.; IR (Film): v{tilde over ( )}=3402, 2115, 1646 (C═O), 1466,1112, 1032, 1014, 747; ¹H NMR (400 MHz, CDCl₃): δ=1.04 (t, J=7.3 Hz, 3,CH₂CH₃), 2.64 (q, J=7.3 Hz, 2H, CH₂CH₃), 3.79-3.92 (m, 4H, CH₂NCH₂),7.22 (d, J=7.8 Hz, 4H, ArH), 7.52-7.56 (m, 4H, ArH), 7.80 (s, 2H,2×C═CHPh) ppm; ESI-MS (m/z): 459.98 (M⁺+H), 461.42 (M⁺+2), 463.12(M⁺+4); Anal. calcd for C₂₁H₁₉Br₂NO: C, 54.69; H, 4.15; N, 3.04; Found:C, 53.81; H, 4.20; N, 3.03.

3,5-Bis(4-cblorobenzylidene)-1-ethylpiperidin-4-one (6b): Yield: 68%;mp: 163° C.; IR (Film): v{tilde over ( )}=2973, 2752, 1614, 1588, 1490,1408, 1310, 1261, 1173, 1095, 987, 824; ¹H NMR (400 MHz, CDCl₃): δ=1.04(t, J=7.3 Hz, 3H, CH₂CH₃), 2.63 (q, J=7.3 Hz, 2H, CH₂CH₃), 3.85 (s, 4H,CH₂NCH₂), 7.30 (d, J=8.2 Hz, 4H, ArH), 7.38 (d, J=8.2 Hz, 4H, ArH), 7.78(s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 372.08 (M⁺+H), 374.46 (M⁺+2),346.22 (M⁺+4); Anal. calcd for C₂₁H₁₉Cl₂NO: C, 67.75; H, 5.14; N, 3.76;Found: C, 67.77; H, 5.17; N, 3.77.

1-Ethyl-3,5-bis(4-fluorobenzylidene)piperidin-4-one (6c): Yield: 79%; mp114° C.; IR (Film): v{tilde over ( )}=2968, 2748, 1676 (C═O), 1617,1600, 1508, 1413, 1225, 1157, 835; ¹H NMR (400 MHz, CDCl₃): δ=1.01 (t,J=7.5 Hz, 3H, CH₂CH₃), 2.62 (q, J=7.5 Hz, 2H, CH₂CH₃), 3.85 (s, 4H,CH₂NCH₂), 7.05-7.07 (m, 4H, ArH), 7.31-7.34 (m, 4H, ArH), 7.78 (s, 2H,2×C═CHPh) ppm; ESI-MS (m/z): 340.14 (M⁺+H); Anal. calcd for C₂₁H₁₉F₂NO:C, 74.32; H, 5.64; N, 4.13; Found: C, 74.32; H, 5.64; N, 4.13.

1-Ethyl-3,5-bis(4-methylbenzylidene)piperidin-4-one (6d): Yield: 71%;mp: 142° C.; IR (Film): v{tilde over ( )}=3026, 2983, 2818, 2748, 1670(C═O), 1604, 1580, 1510, 1260, 1167, 987, 814; ¹H NMR (400 MHz, CDCl₃):δ=1.04 (t, J=7.4 Hz, 3H, CH₂CH₃), 2.38 (s, 6H, 2×PhCH₃), 2.60 (q, J=7.4Hz, 2H, CH₂CH₃), 3.86 (s, 4H, CH₂NCH₂), 7.21 (d, J=8.0 Hz, 4H, ArH),7.29 (d, J=8.0 Hz, 4H, ArH), 7.81 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100MHz, CDCl₃): δ=12.35, 21.42, 51.10, 54.29, 129.31, 130.48, 132.43,136.76, 139.32, 187.36 ppm; ESI-MS (m/z): 332.19 (M⁺+H); Anal. calcd forC₂₃H₂₅NO: C, 83.34; H, 7.60; N, 4.23 Found: C, 83.31; H, 7.58; N, 4.25.

1-Ethyl-3,5-bis(4-ethylbenzylidene)piperidin-4-one (6e): Yield: 20%; mp:178° C.; IR (Film): v{tilde over ( )}=3395, 2908, 1593, 1494, 1416,1310, 1174, 1085, 1006, 910, 834, 747; ¹H NMR (400 MHz, CDCl₃): δ=1.04(t, J=7.3 Hz, 3H, CH₂CH₃), 1.23 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₃), 2.60-2.68(m, 6H, CH₂CH₃, 2'PhCH₂CH₃), 3.82 (s, 4H, CH₂NCH₂), 7.23 (d, J=8.0 Hz,4H, ArH), 7.32 (d, J=8.0 Hz, 4H, ArH), 7.79 (s, 2H, 2×C═CHPh) ppm; ¹³CNMR (100 MHz, CDCl₃): δ=12.38, 15.24, 28.68, 51.22, 54.41, 128.05,130.55, 132.48, 132.71, 136.46, 145.46, 187.39 ppm; ESI-MS (m/z): 360.22(M⁺+H); Anal. calcd for C₂₅H₂₉NO: C, 83.52; H, 8.13; N, 3.90; Found: C,83.51; H, 8.10; N, 3.94.

1-Ethyl-3,5-bis(4-propylbenzylidene)piperidin-4-one (6f): Yield: 67%;Yellow liquid; IR (Film): v{tilde over ( )}=2960, 2931, 1656 (C═O),1606, 1585, 1510, 1308, 1279, 1174, 989, 801; ¹H NMR (400 MHz, CDCl₃):δ=0.89-0.95 (m, 9H, CH₂CH₃, 2×PhCH₂CH₂CH₃), 1.54-1.66 (m, 4H,2×PhCH₂CH₂CH₃), 2.55-2.65 (m, 6H, CH₂CH₃, 2×PhCH₂CH₂CH₃), 3.88 (s, 4H,CH₂NCH₂), 7.14 (d, J=8.2 Hz, 4H, ArH), 7.30 (d, J=8.2 Hz, 4H, ArH), 7.77(s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.70, 13.78, 16.03,24.10, 24.46, 37.70, 38.10, 51.56, 52.78, 54.44, 128.32, 128.67, 129.09,129.85, 130.48, 132.48, 136.48, 191.97 ppm; ESI-MS (m/z): 388.26 (M⁺+H);Anal. calcd for C₂₇H₃₃NO: C, 83.68; H, 8.58; N, 3.61; Found: C, 83.70;H, 8.55; N, 3.63.

1-Ethyl-3,5-bis(4-isopropylbenzylidene)piperidin-4-one (6g): Yield: 63%;Yellow liquid; IR (Film): v{tilde over ( )}=2908, 1658 (C═O), 1593,1494, 1416, 1310, 1174, 1085, 1006, 910, 834, 747; ¹H NMR (400 MHz,CDCl₃): δ=1.20-1.29 (m, 15H, CH₂CH₃, 2×PhCH(CH₃)₂), 2.88-292 (m, 4H,CH₂CH₃, 2×PhCH(CH₃)₂), 3.97 (s, 4H, CH₂NCH₂), 7.22-7.26 (m, 8H, ArH),7.78 (s, 2H, C═CHPh) ppm; ESI-MS (m/z): 388.26 (M⁺+H); Anal. calcd forC₂₇H₃₃NO: C, 83.68; H, 8.58; N, 3.61; Found: C, 83.69; H, 8.53; N, 3.65.

3,5-Bis(4-butylbenzylidene)-1-ethylpiperidin-4-one (6b): Yield: 65%;Yellow liquid: IR (Film): v{tilde over ( )}=2957, 2930, 2858, 1672(C═O), 1607, 1586, 1510, 1307, 1263, 1171, 989, 829; ¹H NMR (400 MHz,CDCl₃): δ=0.91 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₂CH₃), 1.04 (t, J=7.3 Hz,3H, CH₂CH₃), 1.33-1.39 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.59-1.63 (m, 4H,2×PhCH₂CH₂CH₂CH₃), 2.61-2.65 (m, 6H, CH₂CH₃, 2×PhCH₂CH₂CH₂CH₃), 3.85 (s,4H, CH₂NCH₂), 7.21 (d, J=8.0 Hz, 4H, ArH), 7.30 (d, J=8.0 Hz, 4H, ArH),7.80 (s, 2H, 2×C═CHPh) ppm; EST-MS (m/z): 416.29 (M⁺+H); Anal. calcd forC₂₉H₃₇NO: C, 83.81; H, 8.97; N, 3.37; Found: C, 83.79; H, 8.98; N, 3.37.

3,5-Bis(4-tert-butylbenzylidene)-1-ethylpiperidin-4-one (6i): Yield:74%; mp: 111° C.; IR (Film): v{tilde over ( )}=2966, 2931, 2873, 1610,1509, 1308, 1262, 1170, 990, 830; ¹H NMR (400 MHz, CDCl₃): δ=1.05 (t,J=7.5 Hz, 3H, CH₂CH₃), 1.33 (s, 18H, 2×PhC(CH₃)₃), 2.59 (q, J=7.5 Hz,2H, CH₂CH₃), 3.84 (s, 4H, CH₂NCH₂), 7.34 (d, J=8.2 Hz, 4H, ArH), 7.42(d, J=8.2 Hz, 4H, ArH), 7.79 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=12.43, 31.14, 31.31, 34.79, 51.30, 54.47, 125.53, 130.38,132.49, 132.58, 136.32, 152.32, 187.44 ppm; EST-MS (m/z): 416.29 (M⁺+H);Anal. calcd for C₂₉H₃₇NO: C, 83.81; H, 8.97; N, 3.37; Found: C, 83.85;H, 9.00; N, 3.40.

1-Ethyl-3,5-bis(4-methoxybenzylidene)piperidin-4-one (6j): Yield: 67%;mp: 156° C.; IR (Film): v{tilde over ( )}=2968, 2933, 1670 (C═O), 1599,1510, 1302, 1256, 1167, 1030, 830, 732; ¹H NMR (400 MHz, CDCl₃): δ=1.04(t, J=7.1 Hz, 3H, CH₂CH₃), 2.62 (q, J=7.1 Hz, 2H, CH₂CH₃), 3.83 (s, 6H,2×PhOCH₃), 3.85 (s, 4H, CH₂NCH₂), 6.91 (d, J=6.8 Hz, 4H, ArH), 7.34 (d,J=6.8 Hz, 4H, ArH), 7.78 (s, 2H, 2×C═CHPh) ppm; EST-MS (m/z): 364.18(M⁺+H); Anal. calcd for C₂₃H₂₅NO₃: C, 76.01; H, 6.93; N, 3.85; Found: C,76.04; H, 6.94; N, 3.84.

Example 3 Synthesis and Characterization of 1-azidobutane (8b) andRelated Compounds (8a-c)

To a mixture of butyl bromide 7b (5 g, 36.49 mmol) in DMF (30 mL)anhydrous K₂CO₃ (15.10 g, 109.48 mmol) NaN₃ (3.08 g, 47.44 mmol) wasadded. The reaction mixture was stirred overnight at 100° C. Then thereaction mixture was extracted with chloroform and organic layer waswashed with water several times to remove DMF. The organic layer wasdried over Na₂SO₄ and excess of solvent was removed under high vacuum toget the compound 8b. Yield: 1.90 g (52%); liquid; IR (Film): v{tildeover ( )}=3336, 3077, 2854, 2110, 1670, 1409, 1339, 1258, 1917, 911; ¹HNMR (400 MHz, CDCl₃): δ=0.92 (m, 3H), 1.31-1.36 (m, 6H) ppm; ESI-MS(m/z): 100.13 (M^(÷)+H).

Example 4 Synthesis and Characterization of1-(prop-2-ynyl)piperidin-4-one (9)

In a typical reaction conditions 4-piperidone hydrochloride monohydrate1 (5 g, 29.13 mmol) was dissolved in 20 ml, biphasic system of CHCl₃:H₂O(1:1). To this mixture, K₂CO₃ (12.06 g, 87.40 mmol) was added followedby the addition of propargyl bromide (5.17 g, 43.85 mmol). The reactionwas stirred at room temperature for 8 h and progress of reaction wasmonitored by TLC. After completion, reaction mixture was extracted withchloroform. Organic layer was dried over Na₂SO₄ and excess of solventwas removed under high vacuum. The compound was purified over silica gel(mesh size 60-120) using EtOAc/hexane as eluent to obtain the compound9. Yield: 3.39 g (67%); liquid; IR (Film): v{tilde over ( )}=3282, 2961,2913, 2813, 2104 (C≡CH), 1714 (C═O), 1473, 1347, 1324, 1193, 1127, 1084,988; ¹H NMR (400 MHz, CDCl₃): 2.28 (t, J=2.5 Hz, 1H, C≡CH), 2.49 (t,J=5.8 Hz, 4H, 2×CH₂CH₂N), 2.89 (t, J=5.8 Hz, 4H, 2×CH₂CH₂N), 3.43 (d,J=2.2 Hz, 2H, NCH₂CaCH) ppm; ESI-MS (m/z): 138.08 (M⁺+H)

Example 5 Synthesis and Characterization of3,5-bis(4-ethylbenzylidene)-1-(prop-2-ynyl)piperidin-4-one (10b) andRelated Compounds (10a-f)

Compound 9 (200 mg, 1.45 mmol) and 4-ethylhenzaldehyde (391 mg, 2.91mmol) were dissolved in 20 mL of EtOH at 0° C. To this reaction mixture,20% solution of NaOH (2 mL) was added dropwise. A yellow compound wasprecipitated out during the reaction, which was filtered and washed withcold Me0H several times. Crude product was then purified over silica gel(mesh size 60-120) using EtOH/hexane as eluent to obtain compound 10b.Yield: 328 mg (61%); mp: 130° C.; IR (Film): v{tilde over ( )}=3292,2963, 2926, 2126 (C≡CH), 1610 (C═O), 1177, 1003, 921, 830; ¹H NMR (400MHz, CDCl₃): δ=1.26 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₃), 2.35 (t, J=2.2 Hz,1H, C≡CH), 2.68 (q, 4H, 2×PhCH₂CH₃), 3.51 (d, J=2.2 Hz, 2H, NCH₂C≡CH),3.90 (s, 4H, CH₂NCH₂), 7.24 (d, J=8.0 Hz, 4H, ArH), 7.32 (d, J=8.0 Hz,4H, ArH), 7.79 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=17.73,31.18, 48.98, 55.93, 77.00, 130.24, 130.58, 133.05, 134.68, 135.06,139.01, 189.27 ppm; ESI-MS (m/z): 370.21 (M⁺+H); Anal. calcd forC₂₆H₂₇NO: C, 84.51; H, 7.37; N, 3.79; Found: C, 84.49; H, 7.34; N, 3.75.

3,5-Bis(4-methylbenzylidene)-1-(prop-2-ynyl)piperidin-4-one (10a):Yield: 58%; mp: 146° C.; IR (Film): v{tilde over ( )}=3284, 3243, 2918,2146 (C≡CH), 1672 (C═O), 1610, 1510, 1315, 1298, 1258, 1195, 1177, 1003,818; ¹H NMR (400 MHz, CDCl₃): δ=2.38 (s, 6H, 2×PhCH₃), 2.35 (t, J=2.2Hz, 1H, C≡CH), 3.51 (d, J=2.2 Hz, 2H, NCH₂C≡CH), 3.90 (s, 4H, CH₂NCH₂),7.21 (d, J=8.0 Hz, 4H, ArH), 7.30 (d, J=8.0 Hz, 4H, ArH), 7.79 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=23.87, 48.98, 55.93, 79.12,131.78, 132.94, 134.64, 134.81, 139.02, 189.07 ppm; ESI-MS (m/z): 342.18(M⁺+H); Anal. Calcd. for C₂₄H₂₃NO: C, 84.42; H, 6.79; N, 4.10; Found: C,84.45; H, 6.81; N, 4.13.

3,5-Bis(4-isopropylbenzylidene)-1-(prop-2-ynyl)piperidin-4-one (10c):Yield: 58%; mp: 106° C.; IR (Film): v{tilde over ( )}=2926, 2165 (C↓CH),1605 (C═O), 1320, 1264, 1177, 1048, 913, 816, 744; ¹H NMR (400 MHz,CDCl₃): δ=1.25 (d, J=6.6 Hz, 12H, 2×PhCH(CH₃)₂), 2.35 (t, J=2.2 Hz, 1H,C≡CH), 2.89-2.96 (m, 2H, 2×PhCH(CH₃)₂), 3.45 (d, J=2.9 Hz, 2H,NCH₂C═7CH), 3.85 (s, 4H, CH₂NCH₂), 7.20 (d, J=8.0 Hz, 4H, ArH), 7.27 (d,J=8.0 Hz, 4H, ArH), 7.73 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 398.24(M⁺+H); Anal. calcd for C₂₈H₃₁NO: C, 84.59; H, 7.86; N, 3.52; Found: C,84.49; H, 7.83; N, 3.55.

3,5-Bis(4-tent-butylbenzylidene)-1-(prop-2-ynyl)piperidin-4-one (10d):Yield: 56%; mp: 182° C.; IR (Film): v{tilde over ( )}=2958, 2874, 2124(C≡CH), 1672 (C═O), 1611, 1508, 1301, 1257, 1197, 1178, 1013, 825; ¹HNMR (400 MHz, CDCl₃): δ=1.33 (s, 18H, 2×PhC(CH₃)₃), 2.36 (t, J=2.2 Hz,1H, C≡CH), 3.53 (d, J=2.2 Hz, 2H, NCH₂C≡CH), 3.93 (s, 4H, CH₂NCH₂), 7.35(d, J=8.8 Hz, 4H, ArH), 7.44 (d, J=8.8 Hz, 4H, ArH), 7.80 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=31.15, 34.81, 46.55, 53.48,75.68, 125.59, 130.40, 132.34, 136.37, 152.44 ppm; ESI-MS (m/z): 426.27(M⁺+H); Anal. calcd for C₃₀H₃₅NO: C, 84.66; H, 8.29; N, 3.29; Found: C,84.70; H, 8.27; N, 3.27.

1-(Prop-2-ynyl)-3,5-bis(4-propylbenzylidene)piperidin-4-one (10e):Yield: 68%; mp: 96° C.; IR (Film): v{tilde over ( )}=3293, 2958, 2870,2122 (C≡CH), 1672 (C═O), 1610, 1508, 1301, 1257, 1195, 1178, 1003, 824;¹H NMR (400 MHz, CDCl₃): δ=0.87 (t, J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₃),1.56-1.62 (m, 4H, 2×PhCH₂CH₂CH₃), 2.29 (t, J=2.9 Hz, 1H, C≡CH), 2.53 (t,J=7.6 Hz, 4H, 2×PhCH₂CH₂CH₃), 3.46 (d, J=2.2 Hz, 2H, NCH₂C≡CH), 3.85 (s,4H, CH₂NCH₂), 7.16 (d, J=8.0 Hz, 4H, ArH), 7.26 (d, J=8.0 Hz, 4H, ArH),7.73 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 398.24 (M⁺+H); Anal. calcd forC₂₈H₃₁NO: C, 84.59; H, 7.86; N, 3.52; Found: C, 84.61; H, 7.84; N, 3.55.

3,5-Bis(4-butylbenzylidene)-1-(prop-2-ynyl)piperidin-4-one (10f): Yield:57%; semi-solid; IR (Film): v{tilde over ( )}=3285, 2927, 2856, 2135(C≡CH), 1609, 1508, 1458, 1300, 1257, 1177, 1018, 1003, 828; ¹H NMR (400MHz, CDCl₃): δ=0.85 (t, J=7.6 Hz, 6H, 2×PhCH₂CH₂CH₂CH₃), 1.31-1.35 (m,4H, 2×PhCH₂CH₂CH₂CH₃), 1.51-1.56 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 2.29 (t,J=2.2 Hz, 1H, C≡CH), 2.55-2.59 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 3.46 (d, J=2.2Hz, 2H, NCH₂C≡CH), 3.85 (s, 4H, CH₂NCH₂), 7.16 (d, J=8.0 Hz, 4H, ArH),7.25 (d, J=8.0 Hz, 4H, ArH), 7.73 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z):426.27 (M⁺+H); Anal. calcd for C₃₀H₃₅NO: C, 84.66; H, 8.29; N, 3.29;Found: C, 84.70; H, 8.24; N, 3.26.

Example 6 Synthesis and Characterization of1-((1-butyl-1H-1,2,3-triazol-4-yl)methyl)-3,5-bis(4-methylbenzylidene)piperidin-4-one(11b) and Related Compounds (11a-c, 12a-c, 13a-c, 14a-c, 15a-c, 16a-c)

Compound 10a (150 mg, 0.44 mmol) and 4-butylazide 8b (44 mg, 0.44 mmol)were dissolved in 10 mL of t-BuOH at room temperature. To this reactionmixture, mixture of CuSO₄.2H₂O (44 mg, 0.18 mmol) and sodium ascorbate(52 mg, 0.35 mmol) in 10 mL of water was added and reaction mixture wasstirred at 40-45° C. for 3 h. After completion, reaction mixture wasextracted with chloroform and organic layer was dried over Na₂SO₄.Excess of organic solvent was removed under high vacuum. The crudeproduct was purified over silica gel using EtOH/hexane as eluent toobtained compound 136. Yield: 124 mg (63%); mp: 148° C.; IR (Film):v{tilde over ( )}=2927, 1605, 1320, 1264, 1177, 1048, 1000, 913, 816,744; ¹H NMR (400 MHz, CDCl₃): δ=0.75 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₃),1.07-1.15 (m, 2H, NCH₂CH₂CH₂CH₃), 1.62-1.66 (m, 2H, NCH₂CH₂CH₂CH₃), 2.29(s, 6H, 2×PhCH₃), 3.80 (s, 6H, N(CH₂)₃), 4.14 (t, J=6.9 Hz, 2H,NCH₂CH₂CH₂CH₃), 7.13 (d, J=8.0 Hz, 4H, ArH), 7.19 (s, 1H, C═CH), 7.21(d, J=8.0 Hz, 4H, ArH), 7.69 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.73, 21.40, 28.39, 29.75, 50.18, 52.60, 54.67, 122.27,129.27, 129.34, 130.50, 132.29, 136.48, 139.37, 144.40, 187.38 ppm;ESI-MS (m/z): 441.26 (M⁺+H); Anal. calcd for C₂₈H₃₂N₄O: C, 76,33; H,7.32; N, 12.72; Found: C, 76.35; H, 7.34; N, 12.73.

3,5-Bis(4-methylbenzylidene)-1-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(11a): Yield: 59%; mp: 165° C.; IR (Film): v{tilde over ( )}=2925, 2856,1596, 1441, 1265, 1177, 1051, 811; ¹H NMR (400 MHz, CDCl₃): δ=0.73 (t,J=7.3 Hz, 3H, NCH₂CH₂CH₃), 1.66-1.70 (m, 2H, NCH₂CH₂CH₃), 2.30 (s, 6H,2×PhCH₃), 3.81 (s, 6H, N(CH₂)₃), 4.12 (t, J=6.9 Hz, 2H, NCH₂CH₂CH₃),7.13 (d, J=8.0 Hz, 4H, ArH), 7.19 (s, 1H, C═CH), 7.20 (d, J=8.0 Hz, 4H,ArH), 7.70 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 427.24 (M⁺+H); Anal.calcd for C₂₇H₃₀N₄O: C, 76.03; H, 7.09; N, 13.13; Found: C, 76.05; H,7.11; N, 13.14.

3,5-Bis(4-methylbenzylidene)-1-((1-pentyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(11c): Yield: 55%; mp: 169° C.; IR (Film): v{tilde over ( )}=2925, 2855,1670 (C═O), 1606, 1510, 1458, 1320, 1291, 1265, 1177, 1049, 1019, 813;¹H NMR (400 MHz, CDCl₃): δ=0.73 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₂CH₃),1.09-1.19 (m, 4H, NCH₂CH₂CH₂CH₂CH₃), 1.66-1.69 (m, 2H,NCH₂CH₂CH₂CH₂CH₃), 2.30 (s, 6H, 2×PhCH₃), 3.81 (s, 6H, N(CH₂)₃), 4.12(t, J=7.6 Hz, 2H, NCH₂CH₂CH₂CH₂CH₃), 7.12 (d, J=8.0 Hz, 4H, ArH), 7.19(s, 1H, C═CH), 7.20 (d, J=8.0 Hz, 4H, ArH), 7.70 (s, 2H, 2×C═CHPh) ppm;¹³C NMR (100 MHz, CDCl₃): δ=13.73, 21.40, 21.91, 28.39, 29.75, 50.18,52.60, 54.67, 122.27, 129.34, 130.54, 132.29, 136.48, 139.37, 144.40,187.38 ppm; ESI-MS (m/z): 455.27 (M⁺+H); Anal. calcd for C₂₉H₃₄N₄O: C,76.62; H, 7.54; N, 12.32; Found: C, 76.65; H, 7.55; N, 12.35.

3,5-Bis(4-ethylbenzylidene)-1-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(12a): Yield: 65%; mp: 149° C.; IR (Film) v{tilde over ( )}=2962, 2929,2859, 1604, 1445, 1326, 1226, 1179, 1051, 1020, 930, 825; ¹H NMR (400MHz, CDCl₃): δ=0.72 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₃), 1.18 (t, J=7.3 Hz,6H, 2×PhCH₂CH₃), 1.67-1.70 (m, 2H, NCH₂CH₂CH₃), 2.57 (q, 4H,2×PhCH₂CH₃), 3.82 (s, 6H, N(CH₂)₃), 4.13 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₃),7.15 (d, J=8.0 Hz, 4H, ArH), 7.19 (s, 1H, C═CH), 7.23 (d, J=8.0 Hz, 4H,ArH), 7.71 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.75,15.28, 21.91, 28.40, 28.72, 29.75, 50.20, 52.63, 54.71, 122.32, 128.16,130.64, 132.32, 132.53, 136.49, 144.41, 145.65, 187.62 ppm; ESI-MS(m/z): 455.27 (M⁺+H); Anal. calcd for C₂₉H₃₄N₄O: C, 76.62; H, 7.54; N,12.32; Found: C, 76.65; H, 7.55; N, 12.35.

1-((1-Butyl-1H-1,2,3-triazol-4-yl)methyl)-3,5-bis(4-ethylbenzylidene)piperidin-4-one(12b): Yield: 59%; mp: 150° C.; IR (Film): v{tilde over ( )}=2963, 2929,2873, 1670 (C═O), 1606, 1509, 1459, 1327, 1267, 1226, 1226, 1181, 1051,1020, 826; ¹H NMR (400 MHz, CDCl₃): δ=0.74 (t, J=7.3 Hz, 3H,NCH₂CH₂CH₂CH₃), 1.10-1.21 (m, 8H, NCH₂CH₂CH₂CH₃, 2×PhCH₂CH₃), 1.64-1.68(m, 2H, NCH₂CH₂CH₂CH₃), 2.57 (q, 4H, 2×PhCH₂CH₃), 3.83 (s, 6H, N(CH₂)₃),4.14 (t, J=7.7 Hz, 2H, NCH₂CH₂CH₂CH₃), 7.21 (d, J=8.0 Hz, 4H, ArH), 7.17(s, 1H, C═CH), 7.29 (d, J=8.0 Hz, 4H, ArH), 7.72 (s, 2H, 2×C═CHPh) ppm;¹³C NMR (100 MHz, CDCl₃): δ=13.31, 15.29, 19.49, 28.72, 32.02, 49.91,52.62, 54.69, 54.98, 122.32, 128.16, 130.63, 132.32, 132.53, 136.50,144.30, 145.64, 186.88 ppm; ESI-MS (m/z): 469.29 (M⁺+H); Anal. calcd forC₃₀H₃₆N₄O: C, 76.89; H, 7.74; N, 11.96; Found: C, 76.89; H, 7.74; N,11.96.

3,5-Bis(4-ethylbenzylidene)-1-((1-pentyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(12c): Yield: 67%; mp: 156° C.; IR (Film): v{tilde over ( )}=2961, 2928,2858, 1668 (C═O), 1606, 1510, 1462, 1420, 1195, 1177, 1051, 1019, 929,826; ¹H NMR (400 MHz, CDCl₃): δ=0.75 (t, J=6.9 Hz, 3H,NCH₂CH₂CH₂CH₂CH₃), 1.12-1.18 (m, 4H, NCH₂CH₂CH₂CH₂CH₃), 1.19 (t, J=7.3Hz, 6H, 2×PhCH₂CH₃), 1.69-1.73 (m, 2H, NCH₂CH₂CH₂CH₂CH₃), 2.60 (q, 4H,2×PhCH₂CH₃), 3.85 (s, 6H, N(CH₂)₃), 4.15 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₂CH₂CH₃), 7.19 (s, 1H, C═CH), 7.21 (d, J=8.0 Hz, 4H, ArH), 7.27(d, J=8.0 Hz, 4H, ArH), 7.74 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.73, 15.27, 21.90, 28.39, 28.71, 29.74, 50.19, 52.63, 54.70,122.30, 128.15, 130.62, 132.32, 132.53, 144.40, 145.63, 187.40 ppm;ESI-MS (m/z): 483.30 (M⁺+H); Anal. calcd for C₃₁H₃₈N₄O: C, 77.14; H,7.94; N, 11.61; Found: C, 77.15; H, 7.95; N, 11.64.

3,5-Bis(4-isopropylbenzylidene)-1-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(13a): Yield: 55%; mp: 144° C.; IR (Film): v{tilde over ( )}=2959, 2928,2871, 1672 (C═O), 1610, 1508, 1461, 1180, 1051, 1000, 829; ¹H NMR (400MHz, CDCl₃): (t, J=6.9 Hz, 3H, NCH₂CH₂CH₃), 1.19 (d, J=7.3 Hz, 12H,2×PhCH(CH₃)₂), 1.71-1.78 (m, 2H, NCH₂CH₂CH₃), 2.85-2.88 (m, 2H,2×PhCH(CH₃)₂), 3.84 (s, 6H, N(CH₂)₃), 4.14 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₃), 7.20 (d, J=8.0 Hz, 5H, ArH, C═CH), 7.26 (d, J=8.0 Hz, 4H,ArH), 7.74 (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z): 483.30 (M⁺+H); Anal.calcd for C₃₁H₃₈N₄O: C, 77.14; H, 7.94; N, 11.61; Found: C, 77.16; H,7.96; N, 11.66.

1-((1-Butyl-1H-1,2,3-triazol-4-yl)methyl)-3,5-bis(4-isopropylbenzylidene)piperidin-4-one (13b): Yield: 55%; mp: 145° C.; IR (Film):v{tilde over ( )}=2959, 2929, 2871, 1605, 1459, 1325, 1184, 1050, 1019,931, 825; ¹H NMR (400 MHz, CDCl₃): δ=0.74 (t, J=7.7 Hz, 3H,NCH₂CH₂CH₂CH₃), 1.10-1.16 (m, 2H, NCH₂CH₂CH₂CH₃), 1.18 (d, J=7.3 Hz,12H, 2×PhCH(CH₃)₂), 1.64-1.79 (m, 2H, NCH₂CH₂CH₂CH₃), 2.81-2.91 (m, 2H,2×PhCH(CH₃)₂), 3.83 (s, 6H, N(CH₂)₃), 4.14 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₂CH₃), 7.24-7.25 (m, 5H, ArH, C═CH), 7.29 (d, J=8.0 Hz, 4H,ArH), 7.76 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.31,19.49, 23.75, 24.08, 32.01, 33.99, 49.92, 52.80, 54.26, 121.90, 126.75,126.78, 130.67, 132.12, 136.51, 150.1, 187.41 ppm; ESI-MS (m/z): 497.32(M⁺+H); Anal. calcd for C₃₂H₄₀N₄O: C, 77.38; H, 8.12; N, 11.28; Found:C, 77.36; H, 8.10; N, 11.24.

3,5-Bis(4-isopropylbenzylidene)-1-((1-pentyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(13e): Yield: 60%; mp: 143° C.; IR (Film) v{tilde over ( )}=2959, 2931,1672, 1612, 1584, 1461, 1265, 1180, 1051, 1000, 830, 732; ¹H NMR (400MHz, CDCl₃): δ=0.77 (t, J=6.6 Hz, 3H, NCH₂CH₂CH₂CH₂CH₃), 1.07-1.14 (m,4H, NCH₂CH₂CH₂CH₂CH₃), 1.19 (d, J=7.3 Hz, 12H, 2×PhCH(CH₃)₂), 1.67-1.75(m, 2H, NCH₂CH₂CH₂CH₂CH₃), 2.81-2.92 (m, 2H, 2×PhCH(CH₃)₂), 3.88 (s, 6H,N(CH₂)₃), 4.18 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₂CH₂CH₃), 7.24 (d, J=6.6 Hz,4H, ArH), 7.29 (s, 1H, C═CH), 7.30 (d, J=8.0 Hz, 4H, ArH), 7.75 (s, 2H,2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.74, 21.90, 23.74, 28.39,29.74, 33.98, 50.20, 52.68, 54.74, 122.32, 126.74, 130.67, 132.34,132.68, 136.39, 144.42, 150.21, 187.41 ppm; ESI-MS (m/z): 511.34 (M⁺+H);Anal. calcd for C₃₃H₄₂N₄O: C, 77.61; H, 8.29; N, 10.97; Found: C, 77.64;H, 8.25; N, 10.963,5-Bis(4-tert-butylbenzylidene)-1-((1-propyl-1H-1,2,3-triazol-4-yl)methyl)piperidin-4-one(14a): Yield: 69%; mp: 182° C.; IR (Film): v{tilde over ( )}=2905, 2963,2871, 1671 (C═O), 1611, 1462, 1265, 1182, 1000, 834; ^(I)H NMR (400 MHz,CDCl₃): δ=0.66 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₃), 1.24 (s, 18H,2×PhC(CH₃)₃), 1.66-1.70 (m, 2H, NCH₂CH₂CH₃), 3.82 (s, 6H, N(CH₂)₃), 4.09(t, J=7.3 Hz, 2H, NCH₂CH₂CH₃), 7.17 (s, 1H, C═CH), 7.24 (d, J=8.0 Hz,4H, ArH), 7.33 (d, J=8.0 Hz, 4H, ArH), 7.69 (s, 2H, 2×C═CHPh) ppm;ESI-MS (m/z): 511.34 (M⁺+H); Anal. calcd for C₃₃H₄₂N₄O: C, 77.14; H,7.94; N, 11.61; Found: C, 77.11; H, 7.91; N, 11.64.

1-[(1-Butyl-1H-1,2,3-triazol-4-yl)methyl]-3,5-bis(4-tert-butylbenzylidene)piperidin-4-one(14b): Yield: 63%; mp: 145° C.; IR (Film): v{tilde over ( )}=2956, 2928,2858, 1667 (C═O), 1605, 1575, 1511, 1465, 1330, 1269, 1181, 1051, 1020,822; ¹H NMR (400 MHz, CDCl₃): δ=0.72 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₃),1.09-1.18 (m, 2H, NCH₂CH₂CH₂CH₃), 1.26 (s, 18H, 2×PhC(CH₃)₃), 1.65-1.72(m, 2H, NCH₂CH₂CH₂CH₃), 3.81 (s, 6H, N(CH₂)₃), 4.15 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₂CH₃), 7.17 (s, 1H, C═CH), 7.24 (d, J=8.8 Hz, 4H, ArH), 7.33(d, J=8.8 Hz, 4H, ArH), 7.69, (s, 2H, 2×C═CHPh) ppm; ESI-MS (m/z):525.35 (M⁺+H); Anal. calcd for C₃₄H₄₄N₄O: C, 77.82; H, 8.45; N, 10.68;Found: C, 77.80; H, 8.49; N, 10.66.

3,5-Bis(4-tert-butylbenzylidene)-1-[(1-pentyl-1H-1,2,3-triazol-4-yl)methyl]piperidin-4-one(14c): Yield: 61%; mp: 146° C.; IR (Film): v{tilde over ( )}=2959, 2925,2855, 1611, 1459, 1264, 1182, 1016, 1000, 833; ¹H NMR (400 MHz, CDCl₃):δ=0.74 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₂CH₃), 1.07-1.22 (m, 4H,NCH₂CH₂CH₂CH₂CH₃), 1.26 (s, 18H, 2×PhC(CH₃)₃), 1.67-1.75 (m, 2H,NCH₂CH₂CH₂CH₂CH₃), 3.86 (s, 6H, N(CH₂)₃), 4.16 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₂CH₂CH₃), 7.21 (s, 1H, C═CH), 7.28 (d, J=8.8 Hz, 4H, ArH), 7.37(d, J=8.8 Hz, 4H, ArH), 7.72 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.75, 21.91, 28.41, 29.75, 31.13, 34.80, 49.87, 52.31, 54.78,122.35, 125.61, 130.44, 132.31, 132.46, 136.23, 144.79, 152.46, 187.13ppm; ESI-MS (m/z): 539.37 (M⁺+H); Anal. calcd for C₃₅H₄₆N₄O: C, 78.03;H, 8.61; N, 10.40; Found: C, 78.08; H, 8.64; N, 10.44.

1-[(1-Propyl-1H-1,2,3-triazol-4-yl)methyl]-3,5-bis(4-propylbenzylidene)piperidin-4-one (15a): Yield: 69%; mp: 133° C.; IR (Film): v{tildeover ( )}=2955, 2928, 2868, 1604, 1458, 1051, 1019, 806; ¹H NMR (400MHz, CDCl₃): δ=0.77 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₃), 0.91 (t, J=7.6 Hz,6H, 2×PhCH₂CH₂CH₃), 1.60-1.65 (m, 2H, NCH₂CH₂CH₃), 1.72-1.77 (m, 4H,2×PhCH₂CH₂CH₃), 2.56 (t, J=6.9 Hz, 4H, 2×PhCH₂CH₂CH₃), 3.87 (s, 6H,N(CH₂)₃), 4.17 (t, J=6.6 Hz, 2H, NCH₂CH₂CH₃), 7.18 (d, J=8.0 Hz, 4H,ArH), 7.24 (s, 1H, C═CH), 7.27 (d, J=8.0 Hz, 4H, ArH), 7.78 (s, 2H,2×C═CHPh) ppm; ESI-MS (m/z): 483.30 (M⁺+H); Anal. calcd for C₃₁H₃₈N₄O:C, 77.14; H, 7.94; N, 11.61; Found: C, 77.16; H, 7.96; N, 11.64.

1-[(1-Butyl-1H-1,2,3-triazol-4-yl)methyl]-3,5-bis(4-propyibenzylidene)piperidin-4-one(15b): Yield: 67%; mp: 144° C.; IR (Film): v{tilde over ( )}=2957, 2929,2871, 1665 (C═O), 1605, 1575, 1560, 1181, 1050, 1020, 821; ¹H NMR (400MHz, CDCl₃): δ=0.74 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₃), 0.86 (t, J=7.3 Hz,6H, 2×PhCH₂CH₂CH₃), 1.10-1.16 (m, 2H, NCH₂CH₂CH₂CH₃), 1.54-1.69 (m, 6H,NCH₂CH₂CH₂CH₃, 2×PhCH₂CH₂CH₃), 2.51 (t, J=7.7 Hz, 4H, 2×PhCH₂CH₂CH₃),3.82 (s, 6H, N(CH₂)₃), 4.14 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₂CH₃), 7.13 (d,J=8.0 Hz, 4H, ArH), 7.19 (s, 1H, C═CH), 7.22 (d, J=8.0 Hz, 4H, ArH),7.71 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.31, 13.83,19.50, 24.32, 32.02, 37.87, 49.91, 52.55, 54.70, 122.32, 128.75, 130.54,132.30, 132.54, 136.51, 144.16, 187.13 ppm; ESI-MS (m/z): 497.32 (M⁺+H);Anal. calcd for C₃₂H₄₀N₄O: C, 77.38; H, 8.12; N, 11.28; Found: C, 77.34;H, 8.15; N, 11.30.

1-[(1-Pentyl-1H-1,2,3-triazol-4-yl)methyl]-3,5-bis(4-propylbenzylidene)piperidin-4-one(15e): Yield: 59%; mp: 134° C.; IR (Film): v{tilde over ( )}=2956, 2929,2869, 1666 (C═O), 1605, 1560, 1465, 1267, 1179, 1051, 1020, 807; ¹H NMR(400 MHz, CDCl₃): δ=0.74 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₂CH₃), 0.86 (t,J=7.3 Hz, 6H, 2×PhCH₂CH₂CH₃), 1.10-1.19 (m, 4H, NCH₂CH₂CH₂CH₂CH₃),1.55-1.69 (m, 6H, NCH₂CH₂CH₂CH₂CH₃, 2×PhCH₂CH₂CH₃), 2.51 (t, J=8.0 Hz,4H, 2×PhCH₂CH₂CH₃), 3.82 (s, 6H, N(CH₂)₃), 4.12 (t, J=7.3 Hz, 2H,NCH₂CH₂CH₂CH₂CH₃), 7.13 (d, J=8.7 Hz, 4H, ArH), 7.19 (s, 1H, C═CH), 7.22(d, J=8.8 Hz, 4H, ArH), 7.70 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz,CDCl₃): δ=13.83, 21.92, 24.32, 28.41, 29.76, 37.87, 50.21, 52.80, 54.70,122.33, 128.75, 130.55, 132.53, 136.52, 144.18, 187.13 ppm; ESI-MS(m/z): 511.34 (M⁺+H); Anal. calcd for C₃₃H₄₂N₄O: C, 77.61; H, 8.29; N,10.97; Found: C, 77.64; H, 8.27; N, 10.96.

3,5-Bis(4-butylbenzylidene)-1-[(1-propyl-1H-1,2,3-triazol-4-yl)methyl]piperidin-4-one(16a): Yield: 57%; mp: 127° C.; IR (Film): v{tilde over ( )}=2957, 2928,2858, 1666, 1605, 1577, 1465, 1269, 1197, 1179, 1051, 1004, 823; ¹H NMR(400 MHz, CDCl₃): δ=0.74 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₃), 0.85 (t, J=7.3Hz, 6H, 2×PhCH₂CH₂CH₂CH₃), 1.19-1.32 (m, 4H, 2×PhCH₂CH₂CH₂CH₃),1.52-1.55 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.63-1.73 (m, 2H, NCH₂CH₂CH₃), 2.54(t, J=7.3 Hz, 4H, 2×PhCH₂CH₂CH₂CH₃), 3.91 (s, 6H, N(CH₂)₃), 4.12 (t,J=7.3 Hz, 2H, NCH₂CH₂CH₃), 7.14 (d, J=8.0 Hz, 4H, ArH), 7.19 (s, 1H,C═CH), 7.20 (d, J=8.0 Hz, 4H, ArH), 7.82 (s, 2H, 2×C═CHPh) ppm; ESI-MS(m/z): 511.34 (M⁺+H); Anal. calcd for C₃₃H₄₂N₄O: C, 77.61; H, 8.29; N,10.97; Found: C, 77.58; H, 8.31; N, 11.00.

1-[(1-Butyl-1H-1,2,3-triazol-4-yl)methyl]-3,5-bis(4-butylbenzylidene)piperidin-4-one(16b): Yield: 63%; mp: 136° C.; IR (Film): v{tilde over ( )}=2957, 2928,2858, 1666 (C═O), 1605, 1576, 1463, 1330, 1178, 1050, 822; ¹H NMR (400MHz, CDCl₃): δ=0.81 (t, J=7.3 Hz, 3H, NCH₂CH₂CH₂CH₃), 0.89 (t, J=7.3 Hz,6H, 2×PhCH₂CH₂CH₂CH₃), 1.15-1.21 (m, 2H, NCH₂CH₂CH₂CH₃), 1.31-1.37 (m,4H, 2×PhCH₂CH₂CH₂CH₃), 1.56-1.60 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.61-1.71(m, 2H, NCH₂CH₂CH₂CH₃), 2.58 (t, J=7.3 Hz, 4H, 2×PhCH₂CH₂CH₂CH₃), 3.87(s, 6H, N(CH₂)₃), 4.19 (t, J=6.9 Hz, 2H, NCH₂CH₂CH₂CH₃), 7.18 (d, J=8.0Hz, 4H, ArH), 7.24 (s, 1H, C═CH), 7.27 (d, J=8.0 Hz, 4H, ArH), 7.75 (s,2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.31, 13.92, 19.50,22.35, 32.02, 33.36, 35.50, 49.91, 52.31, 54.70, 121.90, 128.69, 130.56,132.30, 132.50, 136.50, 144.39, 187.13 ppm; ESI-MS (m/z): 525.35 (M⁺+H);Anal. calcd for C₃₄HN₄O: C, 77.82; H, 8.45; N, 10.68; Found: C, 77.80;H, 8.43; N, 10.65.

3,5-Bis(4-butylbenzylidene)-1-[(1-pentyl-111-1,2,3-triazol-4-yl)methyl]piperidin-4-one(16c): Yield: 58%; mp: 145° C.; IR (Film): v{tilde over ( )}=2956, 2928,2859, 1665 (C═O), 1604, 1574, 1225, 1051, 822; ¹H NMR (400 MHz, CDCl₃):δ=0.79 (t, J=6.6 Hz, 3H, NCH₂CH₂CH₂CH₂CH₃), 0.89 (t, J=7.3 Hz, 6H,2×PhCH₂CH₂CH₂CH₃), 1.15-1.37 (m, 8H, 2×PhCH₂CH₂CH₂CH₃,NCH₂CH₂CH₂CH₂CH₃), 1.56-1.60 (m, 4H, 2×PhCH₂CH₂CH₂CH₃), 1.67-1.71 (m,2H, NCH₂CH₂CH₂CH₂CH₃), 2.58 (t, J=7.3 Hz, 4H, 2×PhCH₂CH₂CH₂CH₃), 3.87(s, 6H, N(CH₂)₃), 4.17 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₂CH₂CH₃), 7.18 (d,J=8.0 Hz, 4H, ArH), 7.24 (s, 1H, C═CH), 7.27 (d, J=8.0 Hz, 4H, ArH),7.75 (s, 2H, 2×C═CHPh) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=13.75, 13.92,21.92, 22.35, 28.41, 29.76, 33.36, 35.50, 50.21, 53.03, 54.72, 122.31,128.70, 130.57, 132.30, 132.51, 136.48, 144.39, 187.37 ppm; ESI-MS(m/z): 539.37 (M⁺+H); Anal. calcd for C₃₅H₄₆N₄O: C, 78.03; H, 8.61; N,10.40; Found: C, 78.00; H, 8.64; N, 10.43.

Example 7 Evaluation of Cytotoxicity

Cell Culture Methods

Two cell human cancer cell lines were used in this study: human cervicalcancer cells (HeLa) and human embryonic kidney 293 cells (Hek). The celllines were obtained from ATCC (Rockville, Md., USA). Cell lines werecultured at 37° C. and 5% CO₂ in DMEM medium with 10% fetal bovine serum(FBS) and 1% penicillinstreptomycin (all obtained from GibcoBRL, GrandIsland, N.Y.). Cells were passaged three times weekly by trypsinisationwith 0.25% trypsin/0.02% EDTA solution (Sigma) into 75 cm² tissueculture flasks (Nunc, Denamark).

MTT Assay

Both human cervical cancer cells (HeLa) and human embryonic kidney 293cells (Hek) cell lines were seeded into 96-well plate (2.5×10⁴ in 100 μLper well). Testing compounds were dissolved or suspended in DMSO to make10 mM stock solutions. Addition of compounds was performed afteradherent cells reached 40-50% confluence. After incubation for 48 h at37° C. in humidified atmosphere with 5% CO₂, 10 μL of MTT (5 mg/mL inPBS) was added to each well and incubated for another 4 h. The culturemedium was then aspirated and 100 μL of DMSO was added to each well.Optical densities at 490 nm were measured by microplate reader(PERKINELMER VICTOR 3V model 1420). All tests were performed intriplicates. Doxorubicin was used as a positive control and the sameamount DMSO without compound was used as negative control. IC₅₀ valueswere obtained from the curve fitting by using Sigma plot10.

Results

Curcumin analogs (3a-j, 4a-j, 5a-j, 6a-j), (Table 1a) were firstscreened for their cytotoxicity against HeLa cells using the MTT assayat 50 μM (FIG. 1). Promising candidates (OD₄₉₀<0.14) were selected forfurther screening at 20 μM and 2 μM (FIG. 2). Then the top five activecompounds were examined for their IC₅₀ on HeLa and Hek cell lines. Fromthe cytotoxicity data, it is clear that substitution on the nitrogen ofpiperidone with p-toluene sulfonyl (p-Ts), benzene sulfonyl (BS), orethyl (CH₂CH₃) do not play any significant role in cytotoxicity. Forexample, 3a, 4e, and 6g showed very good activity though thesubstitutions are different. However, substitutions on the aromatic ringcould lead to significant differences in IC₅₀ values. Compounds havingp-methyl, p-ethyl, p-propyl, and p-isopropyl groups (3b-d, 3i, 4a-d, 5a,5c-d, 6d) in the aromatic ring showed better effect compared withsubstitutions on the phenyl ring with bulky groups (3g-h, 4g, 5g, 6 h-i)such as p-butyl and p-tert-butyl group (FIG. 2). Among all the testedcompounds, halogen group substitution on the para position, such asp-chloro, p-bromo, and p-fluoro (3a, 3j, 4e, 4i-j, 5b, 5i-j, 6a-c) tendsto confer improved inhibition activity. For example, four of the mostactive compounds 3a, 3j, 4e, and 4i with IC₅₀ values between 0.3-1.5 uMare halogen-containing. Compounds having electron donating groups showedpoor anticancer activity except compound 6g, which showed excellentanticancer activity with IC₅₀ lower than 1 uM against HeLa cancer celllines (FIGS. 2 and 3). Five of the most active compounds 3a, 3j, 4e, 4iand 6g were also tested against the Hek cell lines and these compoundsexhibited excellent cytotoxicity (IC50=1.24-3.54 μM) (FIG. 4, Table 5).As a comparison, doxorubicin had an IC₅₀ of 2.89 μM in HeLa and 0.95 μMin Hek cell lines.

TABLE 5 IC₅₀ (μM) Cell line 3a 3j 4e 4i 6g Hela 0.28 0.61 0.85 1.44 0.86HEK 1.39 1.24 1.97 3.54 1.78

Activity for compounds SR13-17, SR 34, and SR36-40 against HeLa, KB,DU145, and PC3 cell lines is shown in Table 6.

TABLE 6 Compounds SR13 SR14 SR15 SR16 SR17 SR34 HeLa cell 5.3 ± 2.8 2.7± 1.3  2.1 ± 0.35  2.2 ± 0.93 2.5 ± 1.2  2.8 ± 0.93 KB cell  3.7 ± 0.21 1.2 ± 0.32   3 ± 0.31  2.6 ± 0.41 4.3 ± 2.4 4.7 ± 1.1 DU145 cell 6.5 ±3.0 6.6 ± 4.6 3.1 ± 1.3 3.7 ± 2.4 9.6 ± 7.3  4.0 ± 0.49 PC3 cell 3.7 ±2.1  1.5 ± 0.24 3.1 ± 1.8  2.0 ± 0.05  2.8 ± 0.80  2.7 ± 0.80 CompoundsSR36 SR37 SR38 SR39 SR40 Doxorubicin HeLa cell 2.0 ± 1.2 5.0 ± 2.2 2.5 ±1.3 2.6 ± 1.4  1.8 ± 0.65 0.96 ± 0.27 KB cell  1.5 ± 0.30  4.7 ± 0.87 2.1 ± 0.05  2.6 ± 0.69  1.8 ± 0.29  0.4 ± 0.11 DU145 cell  1.9 ± 0.596.7 ± 1.9 6.7 ± 4.4 5.3 ± 2.8  1.9 ± 0.62 0.47 ± 0.25 PC3 cell  1.7 ±0.24 11.0 ± 2.7  2.6 ± 0.4  3.0 ± 0.75  1.8 ± 0.68 0.23 ± 0.01

Similarly, anticancer activity of C5-curcuminoid-triazole conjugateswith their alkyne counterpart (SR11-SR17 and SR34-SR40) was alsoevaluated against HeLa cells. As shown in FIG. 5, most of thesecompounds showed good activity. Therefore, IC₅₀ values were determinedby using four different cell lines (Table 5).

Anticancer activity of compounds SM226, SM229, and SM232 compared todoxorubicin against MOLT 4 and HeLa cell lines as a function of drugconcentration (micromolar) is shown in FIGS. 6 and 7.

1. A compound of Formula I:

wherein R₁-R₁₀ are independently absent or selected from the groupconsisting of substituted or unsubstituted, linear, branched, or cyclicalkyl, alkenyl, or alkynyl; halogen, substituted or unsubstituted arylor heteroaryl; substituted or unsubstituted alkoxy; hydroxy, cyano,formyl, acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primaryamide (including —CONH₂), secondary amide (including —CONHR₁₂), tertiaryamide (including —CONR₁₂R₁₂), secondary carbamate (including —OCONHR₁₂;—NHCOOR₁₂), tertiary carbamate (including —OCONR₁₂R₁₂; —NR₁₂COOR₁₂),urea (including —NHCONHR₁₂; —NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂),carbinol (including —CH₂OH; —CHR₁₂OH, —CR₁₂R₁₂OH), ester (including—COOR₁₂), thiol (—SH), primary amine (—NH₂), secondary amine (including—NHR₁₂), tertiary amine (including —NR₁₂R₁₂), thioether (including—SR₁₂), sulfinyl group (including —SOR₁₂), sulfonyl group (including—SOOR₁₂); R₁₁ is substituted or unsubstituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, or alkynyl; substituted or unsubstituted benzylsulfonyl (Bnz); substituted or unsubstituted p-toluene sulfonyl (p-Ts);substituted or unsubstituted benzyl; substituted or unsubstituted aryl;substituted or unsubstituted heteroaryl; wherein the R₁₁ if substituted,can be substituted with one or more of alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkoxy, amine, halogen, hydroxyl, nitrile, CF₃, ester,amide, urea, carbamate, thioether, carboxylic acid, and aryl and L isabsent or is a linker or spacer.
 2. The compound of claim 1, wherein R₁₁is unsubstituted alkyl, p-toluene sulfonyl, benzyl, or unsubstitutedbenzene sulfonyl.
 3. The compound of claim 2, wherein unsubstitutedalkyl is ethyl.
 4. The compound of claim 2, wherein at least one ofR₁-R₅ and at least one of R₆-R₁₀ are halogen.
 5. The compound of claim4, wherein R₃ and R₈ are chlorine, bromine, fluorine, or combinationsthereof
 6. The compound of claim 2, wherein at least one of R₁-R₅ and atleast one of R₆-R₁₀ are unsubstituted alkyl.
 7. The compound of claim 6,wherein R₃ and R₈ are unsubstituted alky.
 8. The compound of claim 7,wherein the unsubstituted alkyl is methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, or combinations thereof.
 9. The compound of claim 2,wherein at least one of R₁-R₅ and at least one of R₆-R₁₀ areunsubstituted alkoxy.
 10. The compound of claim 9, R₃ and R₈ areunsubstituted alkoxy.
 11. The compound of claim 10, wherein theunsubstituted alkoxy is methoxy.
 12. The compound of claim 1, wherein Lis methylene and R₁₁ is


13. The compound of claim 12, wherein the triazole ring is substitutedat the nitrogen with


14. The compound of claim 1 in Table
 1. 15. The compound of claim 1 inTable
 2. 16. A compound having the formula:

wherein R₁-R₁₀ are independently absent or selected from the groupconsisting of substituted or unsubstituted, linear, branched, or cyclicalkyl, alkenyl, or alkynyl; halogen, substituted or unsubstituted arylor heteroaryl; substituted or unsubstituted alkoxy; hydroxy, cyano,formyl, acyl, carboxylic acid (—COOH), carboxylate (—COO⁻), primaryamide (including —CONH₂), secondary amide (including —CONHR₁₂), tertiaryamide (including —CONR₁₂R₁₂), secondary carbamate (including —OCONHR₁₂;—NHCOOR₁₂), tertiary carbamate (including —OCONR₁₂R₁₂; —NR₁₂COOR₁₂),urea (including —NHCONHR₁₂; —NR₁₂CONHR₁₂; —NHCONR₁₂R₁₂, —NR₁₂CONR₁₂R₁₂),carbinol (including —CH₂OH; —CHR₁₂OH, —CR₁₂R₁₂OH), ester (including—COOR₁₂), thiol (—SH), primary amine (—NH₂), secondary amine (including—NHR₁₂), tertiary amine (including —NR₁₂R₁₂), thioether (including—SR₁₂), sulfinyl group (including —SOR₁₂), sulfonyl group (including—SOOR₁₂), provided that R₃ and R₈ are substituted alkoxy, such as—O(CH₂)_(m)X, where X is halogen or an aromatic or non-aromaticheterocyclic ring, such as

wherein T is O, S, or NR₁₁, wherein each occurrence of R and R₁₁ isdefined as above form R₁-R₁₀; n=0, 2, 3, or 4; m is an integer from0-10; and z, as valence permits, is an integer from 0-10.
 17. Thecompound of claim 16, wherein n is 2 or 3; R₁ is —O(CH₂)₃X, wherein X ishalogen or a heterocyclic ring.
 18. The compound of claim 16, wherein nis 2 or 3; R₁ is —O(CH₂)₃X, wherein X is halogen or a heterocyclic ring;and R₂ and R₉ are other than hydrogen.
 19. The compound of claim 18,wherein R₂ and R₉ are lower alkoxy, such as methoxy.
 20. The compound ofclaim 16 in Table
 3. 21. A pharmaceutical composition comprising thecompound of claim 1 and a pharmaceutically acceptable carrier.
 22. Thecomposition of claim 21, wherein the carrier is suitable for enteraladministration.
 23. The composition of claim 22, wherein the carrier issuitable for oral administration.
 24. The composition of claim 23,wherein the composition is the form of a tablet, soft capsule, hardcapsule, caplet, solution, or suspension.
 25. The composition of claim21, wherein the carrier is suitable for parenteral administration. 26.The composition of claim 25, wherein the composition is in the form of asolution or suspension.
 27. A method of treating a proliferativedisorder in a patient in need thereof, the method comprisingadministering one or more compounds of claim
 1. 28. The method of claim27, wherein the proliferative disorder is cancer.